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",isbn:"978-1-83969-347-2",printIsbn:"978-1-83969-346-5",pdfIsbn:"978-1-83969-348-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"4fc73beb0e4416a20cc70c8163fe436f",bookSignature:"Dr. Pinar Erkekoglu",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9836.jpg",keywords:"KRAS Gene, Oncogene, Tumor Suppressor Gene, Mutation, Cancer, Microtubule-Associated Protein (MAP), GTPase, Pathological Conditions, Epidermal Nevus, Noonan Syndrome, Costello Syndrome, Environmental Chemicals",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 17th 2020",dateEndSecondStepPublish:"December 15th 2020",dateEndThirdStepPublish:"February 13th 2021",dateEndFourthStepPublish:"May 4th 2021",dateEndFifthStepPublish:"July 3rd 2021",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in toxicology, vaccinology, cosmetics, and Board Member of Turkish Pharmacists Association Pharmacy Academia and Board Member of Hacettepe Vaccine Institute. Published more than 150 scientific papers in international/national journals. Associate editor of the Turkish Journal of Pharmaceutical Sciences.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"109978",title:"Prof.",name:"Pinar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pinar Erkekoglu",profilePictureURL:"https://mts.intechopen.com/storage/users/109978/images/system/109978.JPG",biography:"Pınar Erkekoglu was born in Ankara, Turkey. She graduated with a BS from Hacettepe University Faculty of Pharmacy. Later, she received an MSci and Ph.D. in Toxicology. She completed a part of her Ph.D. studies in Grenoble, France, at Universite Joseph Fourier and CEA/INAC/LAN after receiving a full scholarship from both the Erasmus Scholarship Program and CEA. She worked as a post-doc and a visiting associate in the Biological Engineering Department at Massachusetts Institute of Technology. She is currently working as a full professor at Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology. Her main study interests are clinical and medical aspects of toxicology, endocrine-disrupting chemicals, and oxidative stress. She has published more than 150 papers in national and international journals. 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From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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most energy-dependent structures. It demands about 6 kilograms of ATP per day [115]. In order to sustain an efficient energy supply, it has an advanced system producing enough ATP. In the organism, there are two ways to support this demand: production and accumulation. Accumulation is not suitable for the heart due to specific anatomy—most of the cytoplasms consist of myofibrils. According to this fact, in the adult heart, we observe low concentrations of ATP and many ATP-hydrolases. Total resynthesis of all ATP volume takes only 10 seconds in a normal myocardium [32, 55]. Most of the energy resources (~70%) are used for contraction and the rest—for ion pump function (K, Na, Ca pumps ATPases). This system is well coordinated, which helps to maintain the normal flux of energy substrates and ions.
In average, the heart consumes about 20 g of carbohydrates, 30 g of free fatty acids (FFA), and triglycerides (TG). These substrates are oxidized in 35 L of oxygen to produce ATP from ADP [171].
Oxidative phosphorylation of FFA gives about 60% of all produced ATP, while glucose, lactate, and other carbohydrates oxidation produce about 30% of all macroergic compounds. In addition, for energy supplement ketone bodies and amino acids can be utilized. Glucose utilization can be the main energy source in specific conditions (high-carbohydrate diet). Therefore, in understanding myocardial metabolic features, changes during heart failure could provide vital information for early diagnostics and therapy of myocardial diseases [99, 112].
Heart failure syndrome is a consequence of the main heart disease and associated with compensatory mechanism dysfunction, formation, and activation of pathological interactions between components of neurohumoral regulation systems [203]. Decompensation is a condition, which is always connected with reduced energy production and suppressed myocardial metabolism. For example, systolic dysfunction leads to sympathoadrenal system hyperactivation, which is associated with increased heart rate. Catecholamines activate beta-adrenergic receptors, which increase myocardial oxygen consumption due to raised FFA utilization to produce enough energy. This situation leads to increased ADP volume and negative inotropic effect, which is badly tolerated during heart failure and geometrically progress during chronic sympathetic tonus [36, 96, 115, 122, 164].
The main substrates for ATP production are carbohydrates and free fatty acids [98]. In particular, long-chained FFA, glucose, glycogen, lactate, pyruvate, ketone bodies (acetoacetate, beta-hydroxybutyrate), and amino acids (leucine, valine, and isoleucine). These compounds are metabolized to intermediates, which enter the Krebs cycle as an acetyl-coenzyme A (ACoA) or other metabolic equivalents. During substrate utilization, the proton is generated. This proton produces an energetic gradient between mitochondrial membranes, which stimulates the oxidative chain to produce chemical energy and phosphorylate ADP to ATP [60, 61, 171, 184].
Such diversity of substrates for common energy source production predispose to several concepts: (1) myocardial metabolism is very adaptive to organism condition and substrate environment and can vary between main energy resources; unfortunately, in heart failure this flexibility is mostly lost; (2) myocardial metabolism is a self-regulated mechanism; all the intermediates of the tricarboxylic acid cycle are mediators, controlling the main metabolic path and intensity of energy production (Randle cycle); (3) metabolites can be used as components for cell structure resynthesis, and, at the same time, cellular structures could be used as an energetic substrate; (4) metabolic dysfunction and accumulation of metabolites can damage cellular proteins and change the form and function of contractile filaments; (5) myocardial metabolism is not “intracellular chemistry”; this is a functional system, which is presented with specific structure and mediator mechanisms, assessing adaptation of cardiomyocytes to environmental variations [76, 171].
Myocardial metabolism efficiency is highly dependent on pathway and substratesutilized for ATP production. There is a Kyoto Encyclopedia of Genes and Genomes (KEGG) scheme—a collectively designed map of known molecular interactions and feedback systems of energetic metabolism in the myocardium. This map made helps to understand possible ways of energy production in the myocardium and limit its activity [30, 69]. However, we should observe common features of myocardial metabolism.
In aerobic conditions, mitochondrial oxidative phosphorylation is the main source of ATP (about 90%); the rest of macroergic compounds are produced by anaerobic utilization. Mitochondrial oxidative phosphorylation produces energy due to FADH and NADH dehydration, collected from FFA beta-oxidation and, in lesser amounts, other sources. The schematic structure of metabolic interactions designed by Stanley et al. shows the main features of energy production cycles (Figure 1) [140].
Coupled metabolic reactions in the cell and mitochondria in cardiomyocyte [161]. GLUT—glucose transporter, G-6-P—glucose 6-phosphate, MCT—monocarboxylate transporter, PDH—pyruvate dehydrogenase, FAT—fatty acid membrane transporter, TG—triglyceride, and CPT-1—carnitine palmitoyltransferase 1.
Transport of FFA in the cardiomyocyte is presented in two ways: passive diffusion and by specific protein transporters. Long-chained FFA are diffused in the cell, metabolized in acyl-CoA, and transported to the special proteins on the mitochondrial membrane to interact with acetyl-CoA synthase. While active transport, induced by muscle contraction or insulin (Ins) action, is sustained by FATP1, FATP6, and CD36 [78]. These proteins translocate FFA through the membrane, and then couple it with CoA, which is transported to lipid beta-oxidation cycle by carnitine-assosiated translocators [102].
Further, cytosolic carnitine palmitoyltransferase-1 (CPT-1) connects acyl-CoA with carnitine, forming long-chained acylcarnitine. This compound is transported with acylcarnitine translocase through the inner mitochondrial membrane and utilized in FFA beta-oxidation cycles with acetyl-CoA production. Then acetyl-CoA is metabolized in the Krebs cycle to ATP, H2O, and CO2. For example, in the tricarboxylic acid cycle, palmitate is oxidized with 23 moles of O2 to produce 105 moles of ATP [63]. Nevertheless, in comparison with glucose, FFA are not effective energy sources due to their high demand for oxygen. The part of transported FFA is esterified and collected in the cytoplasm as lipid droplets (triacylglycerol-TAG) [68, 100, 101, 181]. TAG-produced ATP is about 10% of all gained ATP in physiological conditions [117]. Also, TAG is an important part of FFA oxidation, in cases when TAG-hydrolase blockade lipid beta-oxidation is severely reduced, which leads to massive lipid droplet accumulation in the cardiomyocytes [46].
The next step is activation of the Krebs cycle. This rotor starts with acetyl-CoA, collected from FFA beta-oxidation or pyruvate decarboxylation. Produced NADH and FADH2 transports are equivalent to electron chain, which stimulates ATP resynthesis in oxidative phosphorylation.
Metabolic pathways of energy production are ruled by directing components (enzymes) and feedback connection (substrate-final product). The mitochondria can bear high-energy demand states, increasing oxygen consumption almost on 85% from the basal level. This ability is very important due to the fact that most of the time it consumes only 25% of the oxidative capacity [111]. Therefore, activation/inhibition of enzymatic systems can control ATP synthesis, and, due to feedback, can correct energetic substrates, in cases of increased metabolites collection or regulation disorders. This kind of metabolic flexibility is very useful in myocardial diseases, associated or modulated by energy resources depletion and absence [31, 32].
In addition, in normal conditions myocardium utilizes lactate, which metabolizes to pyruvate by lactate dehydrogenase and gets involved in the Krebs cycle. In cases of metabolic disorders, the myocardium starts to excrete lactate in the bloodstream. This way appears when there is oxygen deficiency and the energy has to be produced by anaerobic glycolysis (ischemia, terminal stages of cardiomyopathies) [6, 47, 104, 162]. The main transporter controlling excretion and consumption of lactate is the monocarboxylate transporter (MCT). This family consists of four subclasses, in the myocardium only 1 form of MCT-1 is presented. Also, they take a part in ketone body transport [40, 50, 64].
Glycolysis is another coexisting pathway for energy production. The first step of glycolysis starts with glucose transport through the cell membrane by the specific transporter (GLUT). In the cytoplasm glucose is metabolized to pyruvate, which is transported to the mitochondrial matrix by pyruvate dehydrogenase (PDH). Pyruvate is transformed to acetyl-CoA and gets involved to the Krebs cycle [61, 162].
The GLUT family includes 12 classes; the most important for myocardial metabolism are GLUT 1 and GLUT 4, which supplies glucose in the cardiomyocytes. GLUT 4 is insulin dependent and plays a significant role in insulin resistance formation; GLUT 1 is weakly insulin dependent; it is the source of basal glucose transport for myocytes; in addition, it could be additively recruited from cytosol in stress conditions [167]. GLUT 1 is mostly located on the sarcolemma, while GLUT 4 also attenuated to T-tubules, which is useful for “deep” glucose transport during raised energy demand and exercises. In normal conditions GLUT 1 protein expression is higher due to persisting glucose demand as an energy source. GLUT 4 concentration in the myocardium and muscle is almost equal, which means that developing insulin resistance of different etiologies leads to decreased glucose flux both in the skeletal muscle and in the myocardium. GLUT 4 is the main glucose transporter to the muscle cell, but in experiments with GLUT 4 knockout, animals show that glucose can be translocated to the myocyte by different mechanisms [34, 196].
After transport into the cell, glucose was converted to glucose-6-phosphate (G6P) by cytosolic hexokinase 2 (HX2), and then it was utilized in glycolytic reactions or stored as glycogen. Phosphofructokinases—glycolytic enzymes—which irreversibly convert G6P to fructose-6-phosphate, forming fructose-1 and 6-bisphosphate and dephosphorylating ATP to ADP. These kinases are limiting threshold for glycolytic activity and depending on ATP, AMP, citrate concentrations, and pH [131].
After glucose is converted to pyruvate, its metabolism trifurcates to lactate conversion, decarboxylation to acetyl-CoA, and carboxylation to malate or oxaloacetate. Decarboxylation is an irreversible process, catalyzed by pyruvate dehydrogenase (PDH). PDH activation is closely connected with cytosolic Ca+2 and Mg+2 concentrations, sympathetic tonus, while inhibition depends on FFA concentration in the environment. PDH is a multienzyme complex, consisting of two main parts: pyruvate dehydrogenase itself and pyruvate dehydrogenase kinase assessing pyruvate utilization. Pyruvate consumption increases in cases of decreased FAA utilization or artificial inhibition of lipid beta-oxidation. FFA and glucose turnovers in the mitochondria are controlled by the Randle cycle, and by its ways, we could admit that PDH activity is determined depending on the substrate environment (Figure 2) [106, 107, 137, 138].
Pyruvate metabolism in normal myocardium (Stanley et al., 2002).
The lactate-lactate dehydrogenase-pyruvate system is made for additive pyruvate production in cases of high demand or its discharge to lactate when the FFA wing is activated in Randle’s cycle. In heart failure, FAA consumption is increased due to adrenergic hyperactivation and compensatory mechanisms; this leads to PDH inhibition, and glucose metabolites are converted to lactate, instead of pyruvate, and eliminated to the bloodstream. This causes lactate and pyruvate depletion in the cytosol; the relative lactate/pyruvate ration raises and negatively influences energy supplementation for submembrane structures, which control ion recirculation [20, 98, 121, 136, 153].
The final step of glucose utilization is an oxidation of acetyl-CoA to CO2 in the Krebs cycle and formation of 31 ATP molecules. Due to produced ATP amounts, oxidative glycolysis is the most effective energy source.
It should be noted that such intermediates as G6P and lactate can also be metabolized in alternative ways. G6P can be utilized in the pentose phosphate pathway (PPP), producing NADH in association with O2 or a pentose (substrate for nucleotides) in a hypoxic environment. In addition, G6P can be converted to sorbitol, uridine diphosphate-N-acetylglucosamine, which can provide O-associated glycosylation of contractile filaments and Ca+2 ion pumps of the sarcoplasmic reticulum (SR). In cases of massive protein glycosylation, the cell can undergo apoptosis [6, 56, 80, 141].
The intensity of FFA utilization by a healthy myocardium depends on the concentration of non-esterified FFA in the blood, the activity of metabolism modulation mediators (catecholamine, thyroxin, triiodothyronine, insulin, cortisol, adropin) can be increased four times during the day. FFA are transported to cardiomyocytes in non-esterified form, bound with albumin or as chylomicrons, lipoproteins, and then they translocated in the cytoplasm and oxidized. FFA releases are depended on catecholamine-induced activation of hormone-dependent lipase [195]. Therefore, FFA plasma level significantly increased in cases of adrenergic activation, insulin depletion, insulin resistance, hypothyroid condition, hyperadrenocorticism, etc. [98, 128, 201].
In addition, FFA myocardial metabolism is also influenced by secondary messenger, AMP-activated protein kinase (AMPK), which activity is closely connected with the AMP/ATP ratio in the cytosol. This molecule has several actions: (1) AMPK inhibits malonyl-CoA production, switching off acetyl-CoA-synthase, leading to decreased FFA cytosol accumulation; (2) ongoing decrease of malonyl-CoA inhibits bounding of CPT-1 and stimulates transport of acetyl-CoA to the mitochondria for oxidation; and (3) AMPK stimulates expression of FATP and CD36 on cardiomyocyte outer membranes [68, 100, 101, 181].
It should be mentioned that peroxisome proliferator-activated receptor-alpha (PPAR-a) is also a regulator of FFA oxidation. This receptor is a part of ligand-activated family of nuclear receptors. Ligands of the FFA receptor, in active form PPAR-a, activate the synthesis of lipid beta-oxidation enzymes [59]. In experiments, it was observed that this receptor deactivation leads to decreasing FFA oxidation capacity in cardiomyocytes, due to significant depletion of lipid oxidation enzymes. During ischemia and insulin resistance in diabetic mice, induced by streptozotocin, PPAR-a knockout animals were more stable in the ischemia–reperfusion protocol, than the control group mice. This can be explained by the fact that the inhibition of FFA oxidative utilization promotes glycolysis. Inactivated PPAR-a allows to perform increased oxidative glycolysis (decreased FFA oxidation in the Randle cycle), improve GLUT 4 translocation and PDH activation, and improve the severity of insulin resistance. In cases of hypoxic ischemia, this will give a chance for cardiomyocytes’ survival due to glycolysis and energy production. In addition, increased PPAR-a expression promotes GLUT 4 genes suppression, leading to insulin resistance and, indirectly, stimulates FFA oxidation metabolites accumulation, this inhibits glycolysis wing of the Randle cycle, decreases GLUT 4 trafficking activity, and suppresses insulin receptor sensitivity due to PI-3-kinase inhibition [33, 127].
However, in cases of active oxidation in tricarboxylic acid cycle with high production of malonyl-CoA, normal transport of FFA to the mitochondrial inner membrane is stopped. Also, membrane translocation of lipids is inhibited by insulin [28, 72].
Utilization of amino acids (predominately leucine, valine, and isoleucine) in energy metabolism is less effective than glycolysis and FFA beta-oxidation. Active amino acid utilization leads to metabolite accumulation; this state is associated with cardiomyopathies and respiratory chain damage in the mitochondria. Metabolism of this substrate is associated with ketoacid formation; part of them could be converted to acetyl-CoA and used in the Krebs cycle [145].
Another substrate are ketone bodies (beta-hydroxybutyrate and acetoacetate). These compounds are produced by the liver during FFA oxidation, and under normal conditions, their level in the plasma is very low, and so they do not actively utilize in myocardial energy metabolism. However, lipomobilization and insulin depletion (diabetes mellitus) could be exceptions for this situation; this condition leads to decreased glycolysis and lactate consumption by cardiomyocytes. In addition, ketone body utilization inhibits FFA oxidation, altering the process of dissociation of acetyl- CoA to free CoA. This complex promotes secondary to heart failure often noted in patients with diabetes mellitus [49, 95, 160].
In experimental models, it was noted that ketone utilization inhibits lactate oxidation for 30–60% and palmitate for 22%. Later, in vivo experiments admitted that parallel administration of FFA and hydroxybutyrate markedly inhibits FFA oxidation in pigs. It has to be noted that the levels of malonyl-CoA and acetyl-CoA were unchanged. In a similar experiment, it was shown that high concentration of ketone bodies promotes the Krebs cycle blockade and downregulates contractility of cardiomyocytes. So, ketones could be energy substrate to the myocardium, but it blocks other more useful ways of energy production, due to significant demand for oxygen [160, 173].
Some intercellular conditions can influence on metabolism intensity and oxidative potential. The significant parameter of the functional condition of the cell is redox potential. Pyridine compounds (NAD, NADH, NADP, NADPH) play the most important role in this state. One of the simplest estimations of redox potential in a cell is cytoplasmic and mitochondrial NAD/NADH ratio. It is considered that NAD depletion and NADH raise characterize inhibition of oxidation in the mitochondria and slowing of Krebs cycle. This was also noted during hypoxia, enzyme defects, and lack of energy substrates [93].
There are complexes of cytoplasmic oxidoreductase enzymes dependent on NAD concentration. The most active one is lactate dehydrogenase (LDH). LDH, depending on the intracellular environment, can produce NAD and lactate from pyruvate, or reverse this reaction to produce pyruvate and NADH. There are many malate dehydrogenases (MDH) in the mitochondria, which is the part of the malate–aspartate shuttle. In particular, MDH catalyzes the metabolism of oxaloacetate and NADH to malate and NAD, and then malate is transported to the mitochondria, while the NAD/NADH ratio increased in the cytoplasm. In addition, MDH takes part in nitrogen metabolism, rarely can be activated to produce energy from aspartate [12, 67, 85, 146].
High NAD/NADH ratio promotes normal substrate oxidation and saves redox potential to sustain electron transport in oxidative metabolism. As already been said, LDH and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) both use NAD/NADH as a cofactor. GAPDH produces NADH, which is oxidized to NAD by LDH. In anaerobic conditions, both of these enzymes produce NAD, which is utilized in glycolysis. In the aerobic state, NADH reoxidation is connected with its utilization in the mitochondrial respiratory chain. Due to impermeability of mitochondrial membranes to NAD and NADH, there are several shuttles for NADH transport and NAD resynthesis. Discussed above, the malate–aspartate shuttle is predominant in the myocardium [55, 118].
Increased ATP consumption promotes oxidative phosphorylation and increases NAD/NADH ratio. This condition activates several NAD-dependent enzymes: isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, and MDH which increase the Krebs cycle intensity [163, 189].
The main regulator of carbohydrates oxidation is FFA utilization. Increased FFA consumption leads to its intermediate accumulation, which blocks PDH. At the same time, decreased FFA consumption promotes glycolysis and lactate oxidation, due to citrate, NADH, and acetyl-CoA deficiency in the mitochondrial matrix. The last part is often noted in cardiomyopathies and during ischemia [54, 161].
Modern researches showed an impressive role of small molecule proteins—energy homeostasis regulators. Of course, there are many molecules and factors that control energy metabolism, one stimulates appetite (ghrelin, galanin, neuropeptide Y) and another is an anorexigenic (leptin, nesfatin-1) [71, 155]. The first found molecule, which regulates energetic homeostasis, was insulin (Ins); its action was first noted as neurogenic appetite suppression. Later leptin was found—hormone, produced by adipose tissue—and elucidates general adipose tissue state [199]. Then ghrelin and nesfatin-1 were found, with antagonist action to leptin effects on adipose tissue [77, 120]. On the next decades, there was intensive research in the field of lipid homeostasis and appetite-controlling peptides. Many molecules were found; the most important are preptin, irisin, and adropin.
Insulin (Ins) is a hormone with a huge specter of physiological influence, but in this papers, we discuss only three effects: on heart pump function, on Ca+2 ion circulation, and as a mediator between cell communication. Ins-induced transport of glucose is the main mechanism of energy production of membrane-associated ATPases and ion pumps. Controlling pump function, Ins indirectly influences cytoplasmic concentration and equilibration of Ca+2; it mediates cascades of reactions to stimulate Ca consumption or excretion. Ins is involved in endothelial function, regulating NO production and tissue perfusion (including coronary vessels). And, of course, it influences on the contractile ability of cardiomyocytes due to energy metabolism modulation.
As an indirect effect, abilities of Ins to control the availability of energy substrates (effects on liver and adipose tissue) and tissue perfusion should be noted. Ins inhibits TG hydrolysis in adipose tissue (depressing lipomobilizating hormones), decreasing the level of circulating FFA. In addition, reactive Ins secretion increases tissue perfusion due to blood vessels smooth muscle relaxation. This effect plays a significant role during exercise, hypertension, and acute and chronic heart failure [70, 136, 165].
Direct Ins action regulates key enzymes (6-phosphofructokinase 1 and 2, glycogen phosphorylase and synthase, PDH, hormone-dependent lipase, acetyl-CoA carboxylase) and transporters (GLUT family, CPT-1, CD36/FAPT). Interactions between main metabolic substrates (glucose and FFA) are elucidated by Randle’s cycle [136]. Transmembrane glucose transport by GLUT 1 and GLUT 4 is modulated by Ins (both transporters are Ins-determined, but GLUT 1 is less dependent). GLUT 4 is significantly presented in myocardium tissue; this helps to sustain myocardial energy flexibility in exercises and heart failure. Ins influence on glycogen accumulation in several ways: decreasing glucose utilization (FFA oxidation predominance, leads to PDH blockade, glucose intermediates converted to glycogen); HX2 converting capacity in overloaded glucose transport (Ins-dependent GLUT 4 exocytosis); glycogen utilization in glucose depletion. It should be mentioned that glycogen is oxidized more actively, than glucose, due to its already intracellular location and production of more ATP. In addition, Ins stimulates glycogen synthase directly and through G6P raise [52, 86]. Ins and PDH interactions are not clear. We should consider the effects of FFA oxidation suppression (decreased acetyl-CoA concentration in mitochondria), influence on PDH phosphatase, NAD/NADH ratio, and Ca+2 concentration. Generally, Ins is controlling glycolysis indirectly by metabolite and substrate availability and directly through enzymatic systems (mentioned above). Ins’ influence on FFA oxidation is closely connected with its effects on glycolysis and partly described above. By the way, Ins suppresses CPT-1 function, due to malonyl-CoA concentration. It can be explained by the fact that malonyl-CoA is produced by acetyl-CoA carboxylase, which is in direct control of Ins [57, 58].
Mediator effect of Ins between cells is described by its effects on PDH, HX2, phosphofructokinase, glycogen synthase, acetyl-CoA carboxylase, hormone-dependent lipase, PDH kinase, MAP kinase, and lactate intercellular shuttle and based on metabolic influence.
As for leptin, its effects were observed in recent research of dogs with chronic degenerative valve disease. In the experiment the raise of circulating leptin and leptin microRNA in this disease was noted. Observed dogs were not suffering from obesity, so found leptin changes are connected with heart failure syndrome. In addition, the correlation between leptin level and heart failure severity was found [45].
Preptin is a hormone modulating carbohydrate metabolism; it is a part of the insulin family (as insulin, insulin-like growth factor-1, proinsulin-like factor-2, relaxin-2). In experiments, it was found that it is secreted together with insulin and promotes glucose utilization in insulin-like ways. There was a strong connection between preptin expression and insulin resistance. Generally, this hormone plays a role in hepatic glycogenesis and bone density (osteoclasts proliferation) and modulates sensitivity to insulin and adaptation to energetic substrates [1, 10, 126, 186].
Adropin is a recently found hormone controlling lipid metabolism. Adropin regulates energy metabolism, depending on the diet type (significantly raised on a high-fat diet). Systemic administration of adropin decreases hepatosteatosis and hyperinsulinemia severity (moderating carbohydrate-FFA metabolism in peripheral tissues). In researches, a connection between heart failure severity and circulating adropin concentration (high severity of heart failure-high adropin level) was noted. Also in insulin resistance, the level of circulating adropin is decreased and correlated with atherosclerosis risks in diabetes mellitus. Low levels of adropin were associated with endothelial dysfunction and high risk of heart X syndrome. Adropin suppresses the activity of PDH kinase 4, which promotes normal pyruvate utilization in Krebs cycle and decreases CPT-1 activity and traffic of CD36 transporters, decreasing FFA transport in cardiomyocytes. The main functions of adropin consist of regulating NO availability, decreasing lipogenic gene expression, decreasing dyslipidemia and hepatic steatosis, modifying insulin resistance and glucose tolerance, and controlling metabolic homeostasis [37, 38, 39, 82, 91, 168].
Irisin is a hormone controlling the conversion of white to brown adipose tissue. The white adipose tissue has a lack of mitochondria and lots of TG and FFA and produces leptin, ghrelin, nesfatin-1 [15, 27, 135, 178]. While the brown adipose tissue contains lots of mitochondria and lipid droplets. In this cell, high amounts of uncoupling protein-1 are presented. This protein promotes uncoupling of ATP production from FFA oxidation, instead of ADP phosphorylation, and produces heat [62]. In experiments, it was noted that high amounts of circulating irisin are presented in cases of obesity, which can be characterized as irisin resistance (insulin resistance-like) [166]. Irisin is predominantly synthesized in skeletal muscles during exercises. The main actions of this hormone are toward decreasing of white adipose tissue, controlling temperature homeostasis, increasing of glucose tolerance, decreasing obesity, and modulating insulin resistance [144, 198].
Besides, there are also biologically active molecules, which have paracrine effects. This molecule does not affect myocardial metabolism by itself, but promoting reactions could affect the contractile ability of cardiomyocytes. Among them are cytokines, thrombocyte-activating factor (TAF), reactive oxygen species (ROS), arachidonic acid, and nitrogen oxide (NO). The sources of these peptides are the cardiomyocyte itself, endotheliocytes, and migrating immune cells (mononuclear phagocytes, lymphocytes, etc.) [159].
Cytokines include TNF-a, IL-1, and IL-6. TNF-a is produced in cardiomyocytes during injury; the most effects of this peptide are described in ischemia–reperfusion syndrome, due to its significant negative inotropic effect. The main promoters of TNF-a production are hypoxia and ROS. Negative inotropic effect development is staged. First, immediately after the injury, sphingosine is produced from sphingomyelin, which inhibits RyR2 receptors of SR and decreases Ca+2-dependent Ca+2 release, suppressing contractility. In parallel, direct cytotoxic effect developed, due to mitochondrial oxidation uncoupling. And then, NO-dependent Ca+2 transport suppression is developed. Produced NO-superoxide promotes contractile filament damage and cardiomyocyte apoptosis [2, 43, 105, 123, 148].
Interleukins are the main inflammatory mediators; their action closely interacted with TNF-a, developing NO release, suppression of Ca+2 turn over regulation genes and decreasing cAMP in cardiomyocytes [41, 42, 74, 179].
Thrombocyte-activating factor (TAF) is a phosphoglyceride with a potent pro-inflammatory effect. This cytokine is produced by cardiomyocytes, endotheliocytes, and histiocytes. TAF pathological effects are associated with significant vasoconstriction, contractility decrease, ROS, and superoxide release and autolysis activation [35, 48].
Arachidonic acid and its metabolites is part of membrane phospholipids in cardiomyocytes, but in case of injury, these compounds are degraded by phospholipase A2, which is high Ca+2 concentration-dependent. Arachidonic metabolites damage ionic channels components, receptors, intercalated disks and provoke cytoplasmic acidosis, Ca+2 hyperaccumulation [192].
Adenosine is a metabolite of adenine nucleotide; it has a wide specter of action: coronary artery dilatation, negative chronotropic, dromotropic, and inotropic effects by means of A1 and A2 receptors. Adenosine is also a catecholamine antagonist (decreases cAMP activity), stimulates protein kinase C (PKC), promotes macroergic compounds restoration, and inhibits some ROS and neutrophils activity [88, 157].
PKC is a part of intracellular myocardial metabolism regulation. This kinase is sensitive to Ca+2 cytoplasm accumulation, angiotensin II, phenylephrine, and endothelin stimulation. As a response to this stimulation, PKC downregulates troponin; sensitivity of troponin to Ca+2 promotes myofibrillar disruption and decreases contractile ability, fibrosis, and hypertrophy of cardiomyocytes. In experiments, it was noted that increased PKC expression provokes myocardial hypertrophy and fetal metabolic genotype activation and significantly alters Ca+2 ion transmembrane circulation [7, 185, 187]. This can be explained by decreased SERCA2 and phospholamban protein expression, suppression of Na/CA and Na/H ionic pumps, PKC-dependent phosphorylation of the myofilament and troponin proteins, and downregulation of Ca+2-dependent membrane transporters, which indirectly negatively influence on energy metabolism [174].
CaMKK II—calmodulin-dependent kinase— is activated by Ca+2 accumulation in the cytoplasm. CaMKK II independently or by AMPK stimulation promotes GLUT 4 trafficking and exocytosis. In experiments a compound stimulation of GLUT 4 exocytosis and its retention on the outer part of the cell membrane by AMP, PKC, and CaMKK II was elucidated. By these means, muscle contraction promotes GLUT 4 exocytosis and glucose transport, but in cases of pathologic Ca+2 cytoplasm accumulation, GLUT 4 could not move into the cell, which alters glucose consumption and promotes increasing of FFA utilization (Randle cycle). Catecholamine-induced tachycardia provokes altered GLUT 4 endocytosis, insulin resistance, and glycolysis inhibition [90].
As already been said, there are many regulating mediators. However, Ca+2 ions can influence myocardial metabolism by themselves. The raise of Ca cytoplasmic concentration (SR release) is determined by the following mechanisms: Ca+2-dependent Ca+2 release (calcium sparks), SR depolarization, pH changes, voltage-dependent changes of T-tubules and triad membranes, and inositol-dependent release. Calcium provokes GLUT 4 exocytosis and increases glucose consumption. First, this effect was described in experiments with caffeine influence on cardiomyocytes. Myocytes began to utilize glucose, while being incubated with low caffeine concentration.
Nitric oxide decreases cardiomyocyte utilization of glucose due to cGMP effects. In experiments, it was noted that NO-synthase blockade promotes stabilization of ischemic myocardium metabolic state. Some researchers pointed at fact that cGMP and glucose metabolism are not connected, so the real influence of No on metabolism is not clear, but its effects should be noted. In addition, NO has a negative inotropic effect in inhibiting Ca-channel and producing superoxide (peroxynitrite) [17, 18, 19, 83, 170, 197].
Muscle contraction is a multifactor process, including energy status changes (ATP/AMP ratio variation), increased intercellular Ca+2 accumulation, stretch, GLUT 4 exocytosis, glucose and FFA consumption, etc.
Many types of research showed the high effectiveness of myocardial contractility in conditions of intensive glucose utilization, and, at the same time, increased FFA consumption on 26% did not promote equal raise in contractility, but only oxygen demand raised [109, 154]. Target disabling FFA oxidation reactions and FFA bounding to not available compounds decreases oxygen demand and increases the mechanic power of rat’s heart contraction. Combination of insulin and glucose promotes to decrease the heart’s oxygen demand to 39% [79]. These effects are not clearly understood because theoretically palmitate or oleate utilization need fewer molecules of O2 to produce one molecule of ATP in comparison with glucose or lactate. A possible explanation is connected with interactions between long-chained FFA and Ca+2 channels (increases ATP demand for a pump ATP-ase) [75, 109, 154].
Recent studies showed that increased concentration of FFA and TG in the cytoplasm can provoke lipotoxicity in the myocardium, presented in neutral lipids and ceramides accumulation, leading to cell’s apoptosis and decreased contractility. In experiments, Zhou showed that in the diabetic rat, high rates of TG and ceramides were accumulated, promoting DCM-phenotype changes, decreased contractility, and high indexes of cardiomyocytes apoptosis. Nevertheless, in the case of troglitazone, the manifestation of the FFA block mentioned significantly decreased. By this time lipid-induced myocardium remodeling is still mostly unknown, but this process could be associated with cell apoptosis, decreased contractility due to intensive FFA utilization and significantly depressed glycolysis [53, 108, 125, 150, 151, 156, 158, 180, 194, 195].
Heart failure syndrome, despite etiology, development is always associated with an energy deficit. During this state individual cardiomyocytes are under the increased workload associated with the high demand for macroergic substrates, but their production is severely depleted. This state is so-called an engine out of fuel due to decreased amounts of creatine phosphate and ATP [115]. Compensatory and pathological cardiomyocyte hypertrophy is associated with decreased creatine phosphate/ATP ratio, and later ATP decreases too. The creatine phosphate/ATP ratio is a reliable prognostic marker in heart failure worsening [114].
Developing heart failure leads to decreased flexibility of myocardial metabolism. On the certain stages, HF has a tendency to switch FFA utilization as the main energy substrate to glucose oxidation. Decreased FFA consumption, depleted FFA oxidation enzymes, and mitochondrial oxidation biomarkers characterize this stage. This switch is usually early noted. In experiments, it was admitted that metabolic changes in rat myocardium are found in the second week after artificial aortic constriction, while decreased contractility presented only on the 20th week after bandage [24]. Some researchers say that glycolysis predomination is a marker of terminal myocardial metabolism dysfunction. These changes are associated with adaptation because glycolysis demands 12% less oxygen to produce same the amounts of ATP, then FFA oxidation [3, 79].
Transition to glycolysis promotes increased glucose consumption and raised GLUT 1 expression. In parallel, glucose oxidation is also altered, which leads to uncoupling of glycolysis and glucose oxidation. The combination of depressed FFA utilization and glucose oxidation shows decreased mitochondrial oxidative potential ГЛЮТ1 [87, 110].
During glycolysis and glucose oxidation uncoupling, due to PDH inhibition by PDK, pyruvate is not transported to the mitochondria but metabolized to lactate by LDH. This leads to cellular acidosis, and, by the way, this anaerobic glucose utilization gives only two molecules of ATP (while aerobic—32) [103]. Described changes promote cardiomyocyte hypertrophy, energy metabolism depression, ionic pump dysfunction, Ca+2 accumulation, decreased contractility, apoptosis, and fibrosis. It should be noted that this pattern of myocardial dysfunction development is the same for all cardiomyocytes; even in cases of pulmonary hypertension and compensatory hypertrophy of the right heart, metabolic alterations will be identical to the changes observed in the left heart failure [129].
In available data is also admitted that heart failure promotes myocardial tissue insulin resistance, partially due to neurohormonal remodeling, and is an independent predictive factor of sudden heart death in humans [23, 116]. Insulin resistance leads to decreased glucose utilization and ATP production [116, 169]. In some data, it was elucidated that the TG accumulation in muscles (found by 1H NMR method) promotes insulin resistance [81]. The dependence between TG accumulation and insulin resistance is explained by Randle’ cycle: high FFA intracellular accumulation promotes raised acetyl-CoA/CoA and NADH/NAD ratios, which inhibits PDH and leads to citrate accumulation and phosphofructokinase inhibition. Associated G6P accumulation inhibits HX2, promoting intracellular glucose accumulation and decreasing intracellular glucose transport.
Insulin resistance also can be associated with high circulating insulin concentrations. Adrenergic hyperactivity, concomitant to heart failure, leads to increased glucose mobilization, hormone circulation, and insulin synthesis, lipomobilization due to catecholamines (noradrenaline). Insulin stimulates GLUT 4 and CD36 exocytosis, on the first stages it helps to produce enough ATP from glycolysis and oxidative phosphorylation. But insulin receptors have variable action mechanism. Insulin receptors have two places of connection for insulin. One of them has high affinity to hormone and promotes fast response to insulin stimulation; another is a “slow” one and is activated in cases of high insulin concentration and due to geometrical conformation partially blocks the “fast” part of the receptor. In general, insulin resistance is based on the blockade of all “fast” receptors, increased insulin concentration, and fixation of the hormone on “slow” locus of the insulin receptor [9, 11, 13, 14, 94, 116, 152, 175, 190]. Also, a high concentration of circulating FFA decreases insulin-stimulated GLUT 4 translocation. This can be explained by inhibition of Pi 3 kinase of IR-1, which phosphorylation is decreased by TG and phospholipid (FFA-acetyl-CoA, diacylglycerol, ceramides) accumulation in the cytoplasm [26]. GLUT 1 increased expression also takes a part in this process. Increased glucose flux from GLUT 1 promotes decreased GLUT 4 exocytosis and increased GLUT 4 tissue concentration. Developing GLUT 4 function reduction pathological cardiomyocyte hypertrophy and systolic dysfunction occurs [92, 177, 188]. Another factor is pyruvate utilization in anaplerotic reactions, which leads to decreased acetyl-CoA production for Kreb’s cycle, glycolysis and oxidative phosphorylation uncoupling, and PDK 4 activation (promotes inhibition of insulin-stimulated glycolysis) [133].
Also it should be noted that in diabetes and insulin resistance, HX2 activity is decreased. In cell culture experiments, it was found that insulin is HX2 gene expression and protein resynthesis regulator. So, the severity of insulin resistance is a suppressor of HX2 function, leading to G6P accumulation and cytoplasm protein glycosylation. It should be admitted that decreased HX2 microRNA is associated with GLUT 4 genes and protein depletion. These interactions between insulin, HX2, and GLUT can be controlled by insulin sensibilization—by thiazolidinediones (pioglitazone, troglitazone) [124, 132].
Often heart failure is accompanied by all energy-producing enzyme dysfunction. Significant reduction of activity is noted in creatine kinase (CK) function. This enzyme regulates transfer between ATP and creatine. CK is a dimer and consists of two parts M and B, and there are three isoforms: MM, BB, MB, and mitochondrial-CK [193]. MM-CK is closely connected with SR and coupled with Ca+2-ATPase, producing energy for Ca+2 circulation [182]. Mitochondrial-CK is located on the inner membrane of the mitochondria and works with the ADP-ATP translocator. Produced ATP is transported by translocator to mitochondrial-CK and further to creatine phosphate or ADP. This compartment distribution provides effective control of local ATP/ADP ratio and promotes mitochondrial ATP production (decreased ratio) or increases enzymes activity. But in conditions of cardiomyopathy, the normal compartment system is altered. Decompartmentalization leads to uncoupling of the mitochondria—mitochondrial-CK-ATP and phosphocreatine interactions [29, 176].
One experimental research elucidated CK activity in rats with induced heart failure. General CK activity was decreased to 45% from normal value; in particular, the most damaged was mitochondrial isoenzyme (activity was suppressed to 17% of normal). This depletion is connected with mitochondrial dysfunction. Effectiveness of mitochondrial oxygen utilization was experimentally evaluated by ADP concentration changes in presence of creatine. During this experiment, the point of ADP concentration where oxygen utilization does not raise independently to increasing APD was noted. And this level was significantly lower in the heart failure group, but at the same time, the oxidative activity of mitochondria was raised up to 30% higher than in the control group. This data shows inhibition of mitochondrial-CK function, also, indirectly, can show that mitochondrial population is decreased, but its oxidative function is upregulated [184].
CK and mitochondria interactions are very complicated and not only functional but also structural. In the cell, the mitochondria forms a crystal-like structure, predisposed to effectively produce energy sources and preserve contractility. Due to the partial isolation of the mitochondria, the contractile function is controlled by small compartments, surrounding each sarcomere and named “Intracellular Energetic Unit” (IEU). One of the most important roles in this system is played by CK isoenzymes (see above). But destructuration of this compartment will lead to substrate supplementation uncoupling and energy starvation [25, 44, 66, 183].
Heart failure is associated with morphological changes in the mitochondria: size reduction, number increase, edema, cristae deformation, homogenization, and IEU damage. The severity of mitochondrial matrix loss is correlated with heart failure stage, and, in addition, mitochondria size variability characterizes respiratory chain damage [4, 65].
Also, the mitochondria serves as controller of Ca+2 homeostasis in the cytoplasm. The mitochondria regulates Ca-dependent signaling by the means of ion accumulation and energy supplementation for ion pumps, producing an ionic gradient between membranes. The mitochondria directly (SERCA) or indirectly (Na/K pumps) control Ca+2 circulation [16, 119]. Decreased ATP synthesis promotes free Mg+2 accumulation, and its competing effect blocks Ca-dependent Ca release from SR [84]. Then Ca and Na accumulates due to increased activity of Na/H and Na/Ca+2 pumps, provoking acidosis in cardiomyocytes and decreased buffering ability of the mitochondria [200]. Usually, free Mg+2 concentration is low in the cytoplasm, because it is mostly bounded to ATP, but during ATP loss Mg-ion amounts raise. In this way, we can assume that increased intracellular concentration of free Mg+2 is a marker of decreased energy production.
In cases of ATP depletion or oxidative phosphorylation alterations, acidosis is developing. This condition promotes NA accumulation due to activation of Na/H cotransporter. Then inhibition of Na/K pump occurs. While Na accumulates in the cytoplasm, Na/Ca+2 exchange pump activates provoking pathological Ca+2 storage in the cytoplasm, mitochondrial membrane depolarization, and its inability for ionic excess buffering. This condition is predisposing to the accelerated Ca turnover and associated arrhythmias [200].
In general, switching from FFA oxidation to glycolysis during HF characterizes changing of adult heart metabolic pattern to fetal type [97]. This condition leads to disturbances in energy metabolism component gene expression. In experimental models of HF, isogenies, which switched from adult to fetal type, were sequenced [8, 149]. This fetal genotype activation promotes myocardial hypertrophy. One study analyzed 13 metabolism regulating components and expression of the atrial natriuretic peptide (ANP) and heavy beta-myosin chains (beta-MHC) in a normal adult, fetal heart, and in heart failure [139]. The ANP was upregulated in fetal and failing heart, but in HF ANP was not bound to fetal gene overexpression. Stretch, adrenergic hyperactivation, and tachycardia were the reasons for increased ANP in failing heart [147]. Beta-MHC expression was predominant in all three groups in comparison with alpha-MHC. Beta-MHC isogenies were downregulated in fetal and failing hearts, but this is connected with myofilament reduction [51, 73]. Alpha-MHC was reduced by more than 30% in both groups in comparison with the adult heart. These changes are explained by less beta-MHC oxygen and energy demand, but its contractility is also low. In addition, in fetal and failing hearts, FFA oxidation enzymes genes were also suppressed [51, 113, 143].
Fetal genotype is conditioned by hypoxic conditions during embryogenesis, and glycolysis is predominating, while after birth energy metabolism is switched to FFA oxidation. In conditions of pathologic hypertrophy, cardiomyocytes again switched to fetal metabolism in order to survive in the hypoxic environment and energy starvation. In cases of hypertension, this switch appears earlier than in cardiomyopathy [172].
In the adult heart GLUT 4 microRNA expression is rising, while GLUT 1 is decreasing in comparison with fetal heart. In the heart, failure version is observed. The same changes were endured by PDK2, PDK 4, and glycogen synthase. During maturation the amount of mitochondria rises, and, in parallel, citrate synthase gene expression increases. But in failing heart, the mitochondria and citrate synthase are depleted [139].
Adrenergic hyperactivation is associated with high amounts of catecholamines circulating, which promotes reactive oxygen spices (ROS) production. In addition, high amounts of ROS are produced not only by direct stimulation (anthracyclines, tachycardia-induced cardiomyopathy, dilated cardiomyopathy, and etc.) but also by cardiomyocytes overstretch (heart failure with volume overload: valvular diseases, inherited defects) [5, 130, 191].
The main ROS are superoxide (−O2), hydrogen peroxide, and hydroxyl radicals (−OH). Increased formation of this compounds promotes lipid membranes perforation of organelles, DNA, and mitochondria injury [202]. Then this leads to a decrease in SR ATPase, Ca+2 pump, and Na/K pump and Ca+2 accumulation in the cytoplasm [21, 22]. Prolonged exposition to H2O2 provokes CA ion oscillations, leading to Ca-dependent protease activation, mitochondrial membranes perforation, and increasing Ca ion flux through mitochondrial membranes. Combinations of these factors provoke myofilament contracture, damage, and petrification of the mitochondria, and proapoptotic factors release [89].
In veterinary literature, there are studies which elucidate some aspects of the antioxidant system and oxidative stress in dogs with the valvular disease. In these studies, an effect of ROS on valvular structures and on pathogenesis was elucidated, but the certain mechanism is still unknown [134, 142].
As described above there are principal differences between healthy and failing hearts; failing hearts have many similarities with fetal heart metabolic profile. The first stages of metabolic adaptation could differ, while the terminal stage of heart failure has a mostly identical phenotype. Unfortunately, myocardial metabolism in veterinary patients with heart failure is not clearly described. We have lack of proper information and can use some information from human medicine studies (mostly on mice and rats and rarely on dogs, cats, ovine, and embryos). Despite new drugs presented on the veterinary pharmacology market, we can treat heart diseases only on clinical stages and do not have pharmacological tools for prophylaxis. Also, we need to provide specific treatment for some inherited forms of myocardial diseases, such as PDK-dependent dilated cardiomyopathy, and identify the role of taurine and carnitine in arrhythmogenic right ventricle dysplasia/cardiomyopathy.
Cytokines are a cell-signaling group of low molecular weight extracellular polypeptides/glycoproteins synthesized by different immune cells, mainly, by T cells, neutrophils and macrophages, which are responsible to promote and regulate immune response (i.e. activity, differentiation, proliferation and production of cells and other cytokines). These polypeptides act on signaling molecules and cells, stimulating them toward sites of inflammation, infections, traumas, acting on primary lymphocyte growth factors and other biological functions. Cytokines may act in the site where they are produced (autocrine action), in nearby cells (paracrine action) or in distant cells (endocrine action). In this sense, they are important in the development and regulation of immune system cells. Different types of cytokines had been discovered, including chemokines, interferons (IFN), interleukins (IL), lymphokines and tumor necrosis factor (TNF) [1, 2, 3, 4].
\nIn this chapter, we describe and review different cytokines. They will be categorized according to their type, followed by presentation of their function and a brief scope: IFN (IFN-α, β and γ), IL (IL-1, IL-2 and others), TNF (TNF-α and TNF-β) and others. A brief explanation of different cytokines activities also will be done, comprising pro- and anti-inflammatory action, cellular immune responses and performance in hematopoiesis. Methods to reach these objectives include a literature search in the most relevant sources of information, including PubMed/Medline, Scopus and Web of Science databases.
\nAs key results, this chapter will provide a better understanding on cytokines types and functions, with organized concepts about this subject. As we aim to provide a comprehensive review of the available data regarding cytokines, this chapter will be a valuable source of information for readers who seek a thorough and structured synthesis on this topic.
\nInterferon family represents a widely expressed group of cytokines. It includes three main classes, designated as type I IFNs, type II IFN and type III IFNs. The two main type I IFNs includes IFN-α (further classified into 13 different subtypes such as IFN-α1, -α2, -α4, -α5, -α6, -α7, -α8, -α10, -α13, -α14, -α16, -α17 and -α21), and IFN-β. The term interferon derives from the ability of these cytokines to interfere with viral replication. Type I IFNs present a potent antiviral effect by inhibiting viral replication, increasing the lysis potential of natural killer (NK) cells and the expression of MHC class I molecules on virus-infected cells, and stimulating the development of Th1 cells. During an infectious process, this type of interferon becomes abundant and is easily detectable in the blood. On the other hand, type II IFN has only one representative, IFN-γ. This cytokine plays a major role is macrophage activation both in innate and adaptive immune responses. Type III IFNs, also denoted IL-28/29, present similar biological effects to type I IFN, playing an important role in host defense against viral infections [5, 6, 7, 8].
\nInterferon was the first described member of the class of protein molecules now known as cytokines. Nowadays, interferons are well known to participate in innate immune system, mediating responses against viral infections. This role of the IFNs was first described in the 1930s, when a research conducted by Hoskins demonstrated that rabbits previously infected by the herpes simplex virus were protected against subsequent infections by the same type of virus. In 1937, a few years after Hoskins’ experiment, Findlay and MacCallum showed that the virus-infected animals were also resistant to infections caused by antigenically different viruses, corroborating and complementing the existing evidence regarding IFNs functions at that time. Their findings, however, were only confirmed in 1957, when Isaacs and Lindenmann, through cell cultures research, demonstrated that cells infected by a virus had the ability to produce a protein that could make other cells resistant to other viruses. Glasgow, in 1966, theorized that the interferon production was not limited to primary infection by viruses, and that this cytokine might play a role following re-infection. Therefore, the concept of “immune induction” of interferon became well established by the end of the 1960s. The early 1970s were marked by two milestone studies, which confirmed the existence of two different categories of interferons, which differed physicochemically and biologically: the immune-induced interferon (currently known as type II IFN) and the classical virus-induced interferon (currently known as type I IFN). In 1980, the terms IFN-α and IFN-β arose to designate the “classical interferons”, which had been obtained in pure forms exhibiting homogeneity. Albeit the “immune-induced interferon” had not been obtained in pure form at that time, it was recognized that this molecule was different from IFN-α and IFN-β, being, therefore, designated as IFN-γ. Despite the markedly difference of this cytokine when compared to IFN-α and IFN-β, IFN-γ was originally classified in the IFN family due to its ability to ‘interfere’ with viral infections, which characterizes the original definition of IFNs. In the last decade, a third type of IFN (type III IFN) has been described, the IFN-λ. This type is also referred as interleukins IL-28A and B (IFN-λ2 and IFN-λ3, respectively), and IL-29 (IFN-λ1) [8, 9, 10, 11].
\nThere are several isotypes of type I IFNs. In humans, there are multiple forms of IFN-α, only one type of IFN-β and additional isotypes, as IFN-δ, IFN-ε, IFN-κ, IFN-τ and IFN-ω (IFN-δ and IFN-τ have been only described in pigs and cattle). This sort of cytokines presents similar structure, binding to the same cell surface receptor, and they are coded by a family of linked genes located on the human chromosome 9 [7, 12].
\nType I IFN synthesis is induced by microbial challenge (i.e., viral and bacterial infections or microbial nucleic acids exposure) when the pattern recognition receptors (PRRs) sense these microorganisms. These receptors can be found in the cytosol or in the endosome. Once a virus infects a cell, the cell activates signals that lead to phosphorylation, dimerization and passage to the nucleus of the interferon response factor 3 (IRF3). Along with IRF3, other transcription factors, such as nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), activate the transcription of IFN-β gene. After this process, secreted IFN-β binds to the interferon receptor (IFNAR) on the surface of the infected cell, producing an autocrine signaling to mobilize other interferon response factors and alter gene expression patterns to provide interferon response. Besides autocrine signaling, IFN-β also binds to the interferon receptor expressed by neighboring non-virus infected cells, acting in a paracrine manner to promote interferon response in order to help these cells to resist viral infection [5, 13, 14].
\nInterferon response comprises a series of reactions that alter the expression of a variety of human genes. These reactions are mediated by the binding with type I interferon receptors, which consists of the IFNAR1 and IFNAR2 transmembrane proteins, and two associated cytoplasmic tyrosine kinases, the Janus kinase 1 (Jak1) and tyrosine kinase 2 (TyK2). In addition to IRF3, another transcription factor induced by interferon response is interferon response factor 7 (IRF7), which is responsible to initiate IFN-α transcription without the need of NF-κB and AP-1. The canonical pathway that mediates the biological effects of IFNs corresponds to the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Both the antiviral and inflammatory effects of IFN-α/IFN-β are specifically mediated by STAT1 and STAT2. This pathway, however, does not work in isolated manner. It extensively communicates with other signal transduction pathways, therefore recruiting several effector molecules to promote a potent effect against viral infections, antiproliferative and antitumor activities, in addition to the immunomodulatory effects. In healthy individuals, these type I IFN genes are strictly regulated, with almost no constitutive IFN-α production [7, 15, 16].
\nA high number of cells produce IFN-α and IFN-β, including macrophages, fibroblasts, and endothelial cells, specialized leukocytes, called interferon-producing cells (IPCs), or natural interferon-producing cells, secrete up to 1000 times more interferon than the others after microbial challenge. These cells, also known as plasmacytoid dendritic cell (pDCs), are present in the blood, comprising less than 1% of the total peripheral blood mononuclear cells. In terms of morphology, they are similar to plasmocytes, another type of cell responsible for the massive production of this cytokine. IPCs express toll-like receptors (TLRs) 6, 7, 9 and 10, which are critical components of innate immunity, acting as pathogen sensors. Toll-like receptors act on innate immunity cells by detecting conserved patterns of pathogenic microorganisms. These cells, when activated by these receptors, lead to maturation of antigen-presenting cells and production of inflammatory cytokines. Hence, IPCs become responsive to a variety of viral infections through quick secretion of massive amounts of type I IFN. In other words, these cells can produce substantial amounts of type I IFN in response to stimulation with a wide range of DNA and RNA viruses, which signal through TLR9 and TLR7, respectively. During an antiviral immune response, therefore, IPCs are able to promote the function of NK cells, B and T cells, and myeloid dendritic cells through type I IFN. IPCs still differentiate into a unique type of mature dendritic cell, which allows the direct regulation of the function of T cells and links innate and adaptive immune responses. This process occurs at a later stage of viral infection [11, 17, 18, 19, 20].
\nThe whole process mentioned above can be summarized through the following explanation. On the first day after stimulation by viral infection (microbial challenge), IPCs produce massive amounts of type I IFN. On the following 2 days, IPCs differentiate into a type of dendritic cell called a plasmacytoid dendritic cell, which maintains the ability to produce interferon. During the infection process, these cells cluster into the T cell areas of the draining lymph nodes. Although there is some similarity between plasmacytoid dendritic cells and myeloid dendritic cells (known as conventional dendritic cells), it is believed that plasmacytoid dendritic cells do not have a substantial involvement in T cell activation in adaptive immunity, which is the main function of conventional dendritic cells. Therefore, in the context of innate immunity, conventional dendritic cells produce relatively small amounts of type I IFN, but produce large amounts of IL-12, a cytokine that interacts with type I IFN to activate the NK cell response to viral infection [7, 11].
\nIFNs, besides being first line of defense against viral infections, play important roles in immunosurveillance for malignant cells. More specifically, type I interferons present a potent antiviral activity, which is associated with several physiological changes. For ease of understanding, the role of type I interferons, in which IFN-α and IFN-β are the major actors, can be divided in three main functions. Firstly, these cytokines stimulate resistance to viral replication in all cells through cellular genes activation, with the consequent destruction of the viral mRNA and inhibition of the viral proteins translation. Secondly, they promote an increase in ligands to NK cell receptors expression in virus-infected cells. Thirdly, they lead to NK cells to eradicate virus-infected cells [8, 21, 22].
\nNK cells are lymphocytes of innate immune system, which provide defense against viral infections by secreting cytokines (mainly IFN-γ) and killing infected cells. When IFN-α or IFN-β bind to interferon receptors on circulating NK cells, these are activated and directed to infected tissues, where they attack virus-infected cells. It is possible to say that NK cells play, in innate immune response, similar functions than cytotoxic T cells in adaptive immune response [23, 24].
\nType II and type III IFNs do not share homogeneity with type I IFN in terms of induction, and the signaling pathways are, therefore, through their own receptors. Nevertheless, the signal pathways involved with type I IFN and type II IFN, as well as the target genes used by these cytokines, somewhat overlap. IFN-γ receptor (IFNGR) is composed by two structurally homologous polypeptides that belong to the type II cytokine receptor family, named IFN-γR1 and IFN-γR2. IFN-γ (originally designated as macrophage-activating factor) binds and induces dimerization of the two receptor chains. This process leads to the activation of JAK1 and JAK2 kinases and, subsequently, to the phosphorylation and dimerization of STAT1, which stimulates the transcription of several genes. The genes induced by this cytokine encode several different molecules that mediate the biological activities of IFN-γ [5, 14, 25].
\nUnlike IFN-α or IFN-β, the gene that encodes IFN-γ is located on the human chromosome 12. This unique specimen of type II IFN is the primary cytokine involved in macrophage activation (named as classical activation) and plays a critical role in immunity against intracellular microorganisms. In innate immune system, IFN-γ is the main cytokine produced by NK cells, acting as a mediator of innate immunity. Despite belonging to the interferon family, IFN-γ does not produce a potent antiviral effect, running primarily as an activator of effector cells of the immune system. In adaptive immunity, IFN-γ is produced by T cells in response to antigen recognition, and its secretion is increased by IL-12 and IL-18. In addition, B cells and professional antigen-presenting cells (e.g., monocyte/macrophage and dendritic cells) are also involved in this cytokine production. While IL-12 and IL-18 control the production of IFN-γ by promoting its synthesis, IL-4 and IL-10 correspond to the negative regulators of type II IFN production [5, 8, 25].
\nRegarding biological activities, both type I and type II IFN are essential in the immediate cellular response to viral infections. IFN-γ acts on immune cell activation and induction of the major histocompatibility complex (MHC) molecules, which is important at a later stage of the response. Thus, this cytokine establishes an antiviral state for long-term control, coordinating the transition from innate to adaptive immunity. IFN-γ plays a role in macrophage activation, triggering microbicide effector functions in these cells. Macrophages activated by IFN-γ promote more intensive pinocytosis and phagocytosis, in addition to an improved microbial killing ability. Furthermore, IFN-γ acts as a cell growth inhibitor and presents the ability of triggering apoptosis [25, 26].
\nIn summary, in the early stages of infection, NK cells are the main producers of IFN-γ, whose major role is macrophage activation. Once activated, macrophages release cytokines that participate in T cells activation, therefore initiating the adaptive immune response. After being produced and entering the infected site, the effector T cells become, in turn, the main source of IFN-γ and cell-mediated cytotoxicity. Besides the effects on host defense, IFN-γ is also involved in the protection against tumor development [5, 26].
\nType III IFN (IL-28/29 or IFN-λ), likewise type I IFN, present antiviral activity. Type III IFN is subdivided in IFN-λ1 and IFN-λ2/3, which are expressed in identical patterns. The signaling pathway related to IFN-λ is similar to IFN-α/IFN-β, involving mechanisms relying on IRFs and NF-κB actions, with the last one playing an essential role in regulating type III IFN expression. Nevertheless, the expression of IFN-λ is more flexible when compared to type I IFN, once it also involves independent actions of NF-kB and IRFs, allowing the production of this cytokine in response to a wider range of stimuli. Most classes of virus and some bacterial products induce IFN-λ expression, and almost all cell types, mostly pDCs, produce type III IFN after virus infection. However, different from the other types of IFN, macrophages are not involved in IFN-λ expression. Regarding biological activities, IFN-λ acts as the first line in host defense against viral infections, besides regulating innate and adaptive immune responses. Recently, a new member of the Interferon Lambda family was identified, the IFN-λ4. This cytokine presents strong antiviral activity and has been recently described to be related to hepatitis C treatment failure. Several in vivo studies have shown that IFN-λ can be developed as a potent antiviral agent, covering a wide spectrum of viral infections, with the additional benefit of not promoting the unwanted pro-inflammatory effects of IFN-α [6, 27, 28, 29].
\nThe first sign that type I IFN was somehow involved with human autoimmune diseases came from the observation of an increased incidence of autoantibodies and autoimmune diseases after type I IFN treatment. Hence, when considering the indication of IFN-α therapy for some conditions (e.g., hepatitis C virus infection), it is important to scrutinize the presence of autoantibodies in the patient, since they may increase the risk for autoimmune disease development with this kind of treatment [14]. As previously mentioned, pDCs are responsible for producing high levels of type I IFN in response to nucleic acid-containing immune complexes through the activation of TLRs 7 and 9 [11]. These immune complexes are prevalent in autoimmune conditions, such as systemic lupus erythematosus (SLE), which makes this process highly relevant for the development of autoimmunity. It has been described that, in autoimmune diseases, several key immune effector cells, such as B cells, T effector cells and regulatory T cells are modulated by IFN-α. Hence, type I IFN plays a substantial role in this kind of condition [16].
\nRegarding type II IFN, IFN-γ may contribute to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis and type I diabetes mellitus. The role of this cytokine in autoimmune diseases (both in promoting and suppressing the condition) has been shown in several mouse models. The administration of IFN-γ at very early stages of experimental autoimmune encephalomyelitis exacerbates the disease, while its administration at a later stage reduces disease severity. Hence, the absence of biomarkers that could indicate the best stage of the disease to initiate IFN-γ treatment consists in a limiting factor for its therapeutic use [25, 26, 30]. This subject will be reported in the topic “Cytokines and autoantibodies”.
\nDue to the ability to increase immune response, type I and type II IFN have been explored in clinical trials as treatments for several conditions. It has been found that these cytokines are involved with the improvement of several conditions, such as hepatitis B and C virus infections, autoimmune diseases and certain types of leukemia and lymphomas. Hence, this class of cytokines, which play a paramount role in the immune system, consist of valuable treatment strategy. Still, in order to obtain full advantage of the therapeutic potential of interferons, further researches are needed to elucidate the core mechanisms of their effects [31, 32].
\nTumor necrosis factor (TNF) is a cytokine that had the name derived from it discovery in 1975 as a molecule that caused in vitro necrosis of tumors. Shortly thereafter, it was observed that TNF expression was promoted by immune system cells. These discoveries were important to a posterior characterizing of the TNF superfamily and the TNF receptor superfamily, which has more than 40 members, being the most outstanding TNF-α (commonly named as TNF) and TNF-β (also named Iymphotoxin), but also including cytokines and membrane proteins that have similar sequence homologies and a homotrimeric pyramidal structure (e.g. CD40 ligand, FAS ligand, OX40 ligand, GITR ligand and other several proteins). The binding of this family of cytokines with their respective receptors triggers especially inflammatory reactions [33, 34, 35, 36, 37] .
\nTNF-β, a type II transmembrane protein, is an important key in the development of lymph nodes and Peyer’s patches, and also for the maintenance of secondary lymphoid organs. The expression of TNF-β is mainly stimulated by lymphocytes. TNF-α will be better described in the following topics [38, 39].
\nAlthough it were discovered many receptors along the decades, two are best known: TNFR1 (55 kD) and TNFR2 (75 kD). Both receptors are plasma membrane trimmers, while TNFR1 is expressed by most human cells and TNFR2 is mainly produced by immune system cells. It is important to mention that TNFR2 have a higher affinity to TNF. They are related to inflammatory reactions, so that a cytokine bind to the receptor, it induces the recruitment of proteins that are important for the process [35, 40] .
\nThe production of this cytokine is performed by different cells from the immune system, which includes T cells, NK cells, macrophages and monocytes. The stimulus for TNF expression includes different factors, such as bind to pathogen lipopolysaccharide (LPS) and other parts with toll-like receptors (TLRs), and also by other cytokines, highlighting IFN-y [33, 35].
\nIt is primary secreted as a nonglycosylated type II membrane protein arranged as homotrimer. TNF membrane releases a trimeric soluble cytokine (a polypeptide that weighs around 17-kDa with triangular pyramid shape) through proteolytic cleavage by metalloprotease TNF-converting enzyme, and this is the circulating form that is found in blood plasma, and that allows a potent capacity to displacement in the body, thus it endocrine function. It is not well defined but from three of these circulating TNF it is possible to polymerize them forming one 51-kD polypeptide which facilitates the binding of the cytokine with three receptors simultaneously [37, 41, 42].
\nTNF have a lot of physiologic multifunction including immune and inflammatory roles and the survival and death of different cells. The main function of cytokine is to attract and activate immune cells to sites of infections and to destroy pathogens, such as bacteria and virus. In this context, TNF stimulate vascular endothelial cells to express adhesion molecules (e.g. selectins and ligands for leukocyte integrins) that allows immune system cells to connect the wall of blood vessels. Additionally, complementing the inflammatory response, TNF induces the production of chemokines that increase the affinity of leukocyte to their ligands, the expression of IL-1 and to activate microbicidal functions of immune system cells. For all TNF importance in the inflammatory reaction, if low quantities of this cytokine are presented in the local, the containment of the infection may be impaired [33, 37, 41, 42, 43].
\nTNF is also well known to act in inflammatory reaction of some autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. Errors in this production are responsible for a considerable number of autoimmune, neoplastic and other diseases. Under these conditions, the treatment of these diseases are based on biologic agents targeting TNF, and thus looking for reducing the number of available TNF molecules or to block it receptors [33, 35, 40].
\nTNF also promotes necrosis of tumor cells by inducing programmed cell death, a cytolytic potential. The activation of apoptosis mechanism is mediated by TNFR1, by stimulating the recruitment of death signaling proteins, such as Fas-associated protein with death, TNFR-associated factor (TRAF)-1 and TNFR-associated death domain protein (TRADD). These intracellular proteins are responsible for the release of other proteins such as pro-caspase-8, which in it activated form activate caspase-3, caspase-6, caspase-7 and other cytosolic substrates. These proteins induce genomic DNA degradation and cell death through interacting with latent DNAse. Evidences also suggest that TNF have the capacity to induce carcinogenesis and to stabilize tumors, an event that it is opposite of the previous explained, by DNA mutations and it mechanism of repair (i.e. genotoxic potential). This is possible due to the activation of NF-κB in tumor cells and by promoting production of IL-6 (a tumor-promoting cytokine), both facilitate metastasis and cancer cells to escape from immune system defense [35, 40, 41, 42].
\nThere are other biological events and actions caused by TNF. When this cytokine is produced in large scale, such as in severe infection, it may induce shock or decrease of blood pressure due to reducing vascular muscle tone and myocardial contractility. Additionally, in high concentrations TNF can reduce blood glucose concentration, and cause intravascular thrombosis (by decreasing anticoagulant capabilities of the endothelium). TNF is also known as an endogenous pyrogen because it promotes fever by stimulating hypothalamus cells to produce prostaglandins [33, 40].
\nInterleukins (ILs) are a group of secreted proteins with diverse structures and functions. These proteins bind to receptors and are involved in the communication between leukocytes. They are intimately related with activation and suppression of the immune system and cell division. The interleukins are synthesized mostly by helper CD4+ T lymphocytes, monocytes, macrophages and endothelial cells [5, 44, 45].
\nInterleukins are named as IL plus a number. Previously, different names were used to refer to the same IL. For instance, IL-1 was called lymphocyte-activating factor, mitogenic protein or T cell replacing factor III. In order to standardize the nomenclature, in 1979, during the Second International Lymphokine Workshop, the term interleukin was introduced. After that, the interleukins started being named consecutively according to the date of their discovery [44, 46, 47].
\nThere have been identified 40 interleukins so far and some of them are further divided into subtypes (e.g. IL-1α, IL-1β). These ILs are grouped in families based on sequence homology and receptor chain similarities or functional properties [5, 44, 48, 49].
\nIn this section, a brief description of various ILs will be presented. Focus will be given to the families of interleukins 1 and 2.
\nInterleukin-1 family is composed by 11 cytokines: 7 ligands with agonist activity (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β and IL-36γ), 3 receptor antagonists (IL-1Ra, IL-36Ra and IL-38) and 1 anti-inflammatory cytokine (IL-37) [44, 50].
\nThe interleukin-1 family started with only two components: IL-1α, IL-1β. Over the years, new IL with similar behavior and/or structure were discovered and added to the family. All the agonists members of this family show pro-inflammatory activity. These cytokines share a common C-terminal three-dimensional structure with a typical β-trefoil fold consisting of 12-β-strands connected by 11 loops, and have identical positioning of certain introns. Considering that, it is plausible to affirm that they probably arose from the duplication of a common ancestral gene [45, 51, 52].
\nAll members of the family except IL-18 and IL-33 have genes encoding on chromosome 2 in a 400 kb region in human species. Despite the fact that all the cytokines are extracellular, they are synthesized without a hydrophobic leader sequence and are not secreted via reticulum endoplasmic-Golgi pathway, with the exception of IL-1Ra. The secretion mechanism of the other members of the family is still not known. These cytokines bind to closely related receptors, and many of the encoding genes are clustered in a short region of chromosome 2. The receptors contain extracellular immunoglobulin domains and a toll/IL-1 receptor (TIR) domain in the cytoplasmic portion [45, 52].
\nIn order to become active, both IL-1α and IL-1β bind to the ligand-binding chain type I (IL-1R1). Then, the co-receptor, termed the accessory protein (IL-1RAcP), is recruited, and together they form a heterodimeric complex. The signaling that will culminate in a variety of inflammatory activities is initiated by the recruitment of the adaptor protein MyD88 to the toll-IL-1 receptor (TIR), which is followed by the phosphorylation of kinases, the translocation of the nuclear factor kappa B (NF-κB) to the nucleus and the expression of inflammatory genes [50, 51].
\nBoth IL-1α and IL-1β have precursor forms. The precursor of IL-1α is present in the epithelial layers of the gastrointestinal tract, lung, liver, kidney, endothelial cells and astrocytes; and it is capable of binding to the IL-1R1 and initiating the signaling cascade, essentially after cell death by necrosis (e.g. myocardial infarction and stroke). On the other hand, the precursor of IL-1β is not active and does not bind to the receptor. It requires a cleavage to become in the active form [44, 50, 51].
\nIL-1β is highly involved with autoimmune, infectious, degenerative and, especially, with autoinflammatory diseases. An important part of autoinflammatory diseases is caused by genetic defects in innate inflammatory pathways, and usually show their signals early in life. The first disease classified as autoinflammatory was tumor necrosis factor receptor associated periodic syndrome (TRAPS). Other examples are familial Mediterranean fever and adult and juvenile Still disease. This group of diseases promptly responds to the treatment with IL-1β blockade, with few exceptions. In many autoinflammatory diseases, there is a state of increased release of IL-1β. The precursor is converted to the active form through the action of Caspase-1. This enzyme is also found in the inactive form in tissue macrophages and dendritic cells, and requires conversion by autocatalysis to become active. However, it is in the active form in circulating human blood monocytes. The release of IL-1β from blood monocytes in highly controlled and takes several hours in healthy subjects. In patients with an autoinflammatory disease, more mature IL-1β is released when compared to healthy subjects, which leads to exacerbated inflammation. Despite of this group of diseases being characterized by severe inflammation, the amount of IL-1β released is not much greater than that released from healthy subjects. Currently, human anti-IL-1β monoclonal antibody is being developed to treat autoinflammatory diseases. Canakinumab was approved by Food and Drug Administration (FDA) in 2009 for the treatment of cryopyrin-associated periodic syndromes (CAPS). In 2016, Canakinumab was also approved for treating TRAPS, hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD) and familial Mediterranean fever (FMF) [50, 51].
\nIL-1Ra is a receptor antagonist. It is synthetized by the same cells that produce IL-1α and IL-1β (monocytes, macrophages, dendritic cells and others). The binding of IL-1Ra to the receptor does not involve conformational change and, hence, the co-receptor IL-1RAcP is not recruited. IL-1Ra regulates the activity of IL-1. However, to efficiently block the IL-1 response, it has to be in an amount approximately 100-folds greater than the agonists cytokines. Anakinra is a recombinant version of IL1-Ra used in the treatment of rheumatoid arthritis [44, 53].
\nIL-18 is synthetized as an inactive precursor, and, similarly to IL-1β, it needs cleavage by caspase-1 to become in the active form. The precursor form is present in almost all cells of the human body, likewise IL-1α. Usually diseases related to IL-18 appear when there is an imbalance between the amount of IL-18 and IL-18 binding protein, which is responsible for limiting the level of activity of IL-18. This cytokine is released usually from dying cells, once again like IL-1α [51, 54].
\nIL-18 was first described as “IFN-γ-inducing factor”, because it was discovered as an inducer of IFN-γ production. However, alone, IL-18 does not induce the production of considerable amounts of IFN-γ. For that to happen, it has to act in association with IL-12. IL-18 promotes TH1 and Th2 cells responses, and also induces IL-13 production in T cells and NK cells together with IL-2. It also enhances NK toxicity by promoting the expression of Fas ligand in NK cells. IL-18 is involved in several autoimmune diseases, in myocardial infarction, metabolic syndromes and others [44, 55].
\nIL-33 is an alarmin cytokine, rapidly released upon cellular damage. It is involved mainly in type 2 immunity and inflammation. It acts in Th2, in innate lymphoid cell-2 (ILC2), and in activated M2 polarized macrophages. This cytokine is expressed by keratinocytes, epithelial and endothelial cells, and monocytes. IL-33 is produced as a precursor, but, contrary to IL-1, caspase-1 transforms it in an inactive cytokine. The precursor is active and other proteases can cleavage it in more potent forms. IL-33 induces Th2 response binding to ST2 and next recruiting IL-1RacP. The activity of IL-33 is controlled essentially by the binding to soluble ST2 and soluble IL-1RAcP. Levels of increased soluble ST2 are present in various inflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis [44, 50, 56].
\nIL-36α, IL-36β and IL-36γ are receptor agonists, while IL-36Ra is a receptor antagonist that blocks the activation of the receptor and competes with IL-36, acting as a regulator. These cytokines are included in the interleukin-1 family because they share homology to the first members of the family. Their homology to IL-Ra and IL-1β varies from 20 to 52%. Furthermore, IL-36β and IL-36γ have the core 12-fold, β-trefoil structure and lack a signal peptide, particular features of IL-1 family. All these cytokines need an N-terminal processing to become in the active form, but the enzyme responsible for this process is still not known. IL-36 cytokines are predominantly found in skin cells, and that is why they are related with several skin disorders, such as psoriasis. After binding to the receptor (IL-36R and IL-1RAcP co-receptor), dendritic cells are activated and participate in the polarizing of T-helper responses [50, 52, 57].
\nDifferent from the other members of the family, IL-37 is an anti-inflammatory cytokine, and reduces innate inflammation as well as acquired immune responses. Its presence has already been reported in skin, tonsils, esophagus, placenta, breast, prostate and colon. There are five different isoforms of IL-37: IL-37a, IL-37b, IL-37c, IL-37d and IL-37e, expressed in different locations of the human body. So far, IL-37b, which contains a 12β-strand trefoil, typical of the IL-1 family, appears to be the most biologically active, and therefore the object of the majority of studies. IL-37 suppresses the production of pro-inflammatory cytokines, such as IL-1A, IL-6, CC chemokine ligand (CCL-12), colony-stimulating factors (CSF-1 and CSF-2), chemokine ligand-13 (CXCL-13), IL-1β, IL23-A and IL1RA, and also inhibits dendritic cell activation [58, 59, 60].
\nIL-38 is the most recent member of the Interleukin-1 family, identified in 2001. It binds to the same receptor that the IL-36 cytokines, IL-36R. However, it acts as an antagonist, similarly to IL-36Ra. Therefore, IL-38 acts reducing inflammatory response. IL-38 shares 41% homology with IL-1Ra and 43% with IL-36Ra. This cytokine is present in skin, tonsil, thymus, spleen, fetal liver and salivary glands. The properties and biological activities of IL-38 are still being studied [52, 61, 62].
\nThe IL-2 cytokine family, also known as the common γ-chain family, is composed by ILs 2, 4, 7, 9, 15 and 21. All these ILs bind to the common γc receptor, also called CD132. These cytokines act as growth and proliferation factors for progenitors and mature cells [44, 63].
\nIL-2 is the first member of the common γ-chain family, previously known as T cell growth factor. This cytokine is mainly produced by CD4+ and CD8+ T cells, but can be also expressed by dendritic cells and NKs. The IL-2R is composed by three subunits (CD25, CD122 and common γc), all necessary to binding to IL-2. IL-2 acts in the development of regulatory T (Treg) cells, as a B cell growth factor, stimulates antibody synthesis and promotes proliferation and differentiation of NK cells and T helpers. IL-2 has been extensively used as an anti-cancer therapy [44, 63, 64, 65].
\nIL-4 is produced by Th2 cells, basophils, eosinophils and mastocytes. It has two receptors: IL4-R type I, which binds only to IL-4 and is composed by CD124 (IL-4rα) and CD 132; and type II, which binds to IL-4 and to IL-13, and it consists in IL-4Rα and IL-13Rα1. These receptors are spread all over the human body. IL-4 is known to play several different roles, regulating allergic conditions and activating the immune response against extracellular parasites (B cell class switching to IgE). It is the main cytokine to stimulate development of Th2 cells. Dupilimab is an IL-4 receptor antagonist approved in 2017 by FDA for treatment of eczema [44, 66, 67].
\nIL-7 is a homeostatic cytokine. It can be found essentially in T cells, progenitors of B cells and bone marrow macrophages. As the other members of the family, its receptor (IL-7R) consists in the common γ-chain fraction, along with another unit, the IL-7Rα (CD127). IL-7 is involved in the survival and proliferation of thymocytes and in the development of naïve and memory B and T cells, mature T cells and NKs. Deficiencies related to IL-7 result in immunodeficiency, autoimmune diseases and leukemia [44, 68].
\nIL-9 is mainly produced by Th2 cells, but it is also expressed in less amounts by eosinophils and by mastocytes of asthmatic patients. Its receptor, IL-9R, is composed by the CD132 and IL-9Rα units. IL-9 is a potent growth factor for T cells and mastocytes, and some of it activities include the inhibition of cytokine production by Th1 cells, IgE production, and mucus secretion by bronchial epithelium. Recently, a new subset of effector T cells was discovered, Th9, and it is believed that it is intimately related with IL-9 production. IL-9 is associated to allergic diseases and protection from helminthic infections. This cytokine can be found in elevated amounts in Hodgkin lymphoma, hence, IL-9 antagonists are being studied as a potential treatment for this disease [44, 69, 70].
\nIL-15 is structurally homologous to IL-2. The receptor, IL-15R, is composed by the CD132 subunit common to the family, and also by IL-15Rα and IL-2Rβ chains. IL-15 is produced by keratinocytes, skeletal muscle cells, monocytes and activated CD4+ T cells, in response to signals that trigger innate immunity. IL-15 has some identical functions to IL-2, such as T cell activation and stimulation of NK cell proliferation, but it also involved with CD8+ memory cell, NK cell, and NKT-cell homeostasis. Increased levels of IL-15 were reported in autoimmune disorders, such as rheumatoid arthritis, psoriasis and celiac disease [44, 71].
\nIL-21 is produced by T cells, NKT cells and Th17. The receptor, IL-21, is present in various parts of the human body and consists in CD132 and IL-21R. This cytokine is involved with B cells functions, and also increases the proliferation of CD8+ T cells, NK cells and NKT. IL-21 is currently being studied as anti-cancer therapy [44, 64].
\nIn addition to the aforementioned cytokines, other also deserves attention, such as chemokines. The chemokines represent a large family of structurally homologous cytokines that stimulate leukocytes movement and regulate the migration of them from the blood to tissues, in a process named chemotaxis. They control homeostatic immune cells, such as neutrophils, B cells, and monocytes, trafficking between the bone marrow, blood and peripheral tissues. Therefore, they can be classified as chemotactic cytokines [33, 72].
\nThere are about 50 human chemokines, classified into 4 families according to the location of N-terminal cysteine residues. The two major families are CC and CXC chemokines, in which the cysteine residues are adjacent on CC family, and are separated by one amino acid on CXC family. In general, members of CC chemokines are chemotactic for monocytes, and a small subset of lymphocytes, while CXC chemokines are more specific for neutrophils. The best-known chemokine is IL-8, or CXCL8, which belongs to the CXC chemokine family, and is responsible for neutrophil recruitment and for the maintenance of the inflammatory reaction. On the other hand, the monocyte chemoattractant protein-1 (MCP-1) or CCL2, and CCL11 or eotaxin, are examples of CC chemokines, which acts on recruitment of a variety of leukocytes, but especially monocytes, and eosinophils, respectively [33, 73, 74].
\nThe chemokines receptors are expressed on all leukocytes and are divided in two groups: G protein-coupled receptors with seven-transmembrane α-helical segments, and atypical receptors, which appear to attenuate inflammation by scavenging chemokines, independently of G protein. Each receptor subtype is capable of binding to various chemokines of the same family, and a single chemokine can bind to more than one receptor. Despite of this factor, a lot of chemokines presents a great tissue and receptor specificity [72, 73].
\nChemokines can be produced constitutively in various tissues, and are responsible for regulating the traffic of leucocytes, especially lymphocytes, through peripheral lymphoid tissues. However, the best-known activity of chemokines is the involvement on inflammatory reactions. Recruitment of macrophages, neutrophils and T cells to the site of inflammation is strongly stimulated by chemokines. In fact, they represent a secondary pro-inflammatory mediator that is induced by primary pro-inflammatory mediators, such as IL-1 or TNF. In general, members of the chemokines family induce recruitment of well-defined leukocyte subsets, differently of the classic leukocyte chemoattractants. They induce the movement of leukocytes, and consequently promote their migration to a specific local, by stimulating actin filaments [33, 72, 73, 74].
\nBeyond the involvement of the chemokines on acute inflammatory reactions, and the regulation of the traffic of leukocytes through peripheral lymphoid, independently of the presence of inflammation, some kind of chemokines can promote angiogenesis and wound healing, associated mostly with CXC family, while other are involved in the development of diverse nonlymphoid organs [73, 74]. They also have an important role in the priming of naive T cells, in effector and memory cell differentiation, and in regulatory T cell function [72].
\nBesides chemokines, there are cytokines that stimulates hematopoiesis, such as the colony-stimulating factors (CSFs), which contributes to the growth of progenitors of monocytes, neutrophils, eosinophils and basophils, as well as activating macrophages. Immune and inflammatory reactions uses leukocytes, due to the recruitment induced by some kinds of cytokines, so new must be produced [73, 74]. Additionally, the GM-CSF (granulocyte-macrophage colony-stimulating factor) and M-CSF (macrophage colony-stimulating factor) have, like some other cytokines, a pro-inflammatory action, and exhibit a connexon between the expression of them and TNF, IL-1, IL-23 and IL-17 [75].
\nFinally, other cytokines can be highlighted: TGF-β, LIF, Eta-1 and oncostatin M. The TGF-β is responsible for the chemoattraction of monocytes and macrophages, but also it has an anti-inflammatory effect, by inhibiting the lymphocyte proliferation. LIF and oncostatin M induce the production of acute-phase protein, while Eta-1 stimulates the production of IL-2, and inhibits the production of IL-10 [73].
\nOn this topic, the association between the cytokines and autoimmune diseases will be reviewed, but emphasis will be given to these ones: systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis, vitiligo and heart failure.
\nThe impossibility of differentiating between own and non-own (strange) could result in the synthesis of antibodies against the components of the organism (autoantibodies), which could be extremely deleterious [73]. The organism is characterized by a failure of the normal mechanism of self-tolerance, resulting in reactions against one’s cells, in the absence of any present infection or another cause, known as autoimmunity, and the diseases caused by this phenomenon are referred as autoimmune diseases [33, 76].
\nThe pathogenesis of autoimmune diseases involves mainly the genetic susceptibility, and previous infections. In relation to infections, it is observed a recruitment of leukocytes into the affected tissue, resulting in the activation of tissue antigen-presenting cells (APC). Consequently, these APCs express costimulators and secrete T cell-activating cytokines, contributing to the breakdown of T cell tolerance. Therefore, the infection promotes the activation of T cells that are not specific for the pathogen, in a process called bystander activation. Additionally, microbes may engage toll-like receptors (TRLs) on dendritic cells, resulting on production of lymphocyte-activating cytokines, leading to the autoantibody production. This process was demonstrated in mouse models, and its influence in human autoimmune diseases remains unclear [33].
\nThe systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by the involvement of immune complexes formed from autoantibodies and their specific antigens that are responsible for the clinical manifestation, especially glomerulonephritis, arthritis and vasculitis. The peripheral blood lymphocytes of patient presents an excessive production and response to type 1 IFNs, but the involvement of this cytokines on the development of the diseases is still uncertain [33]. In these patients, for instance, serum IFN-α and IFN-α-induced gene expression are frequently observed, implying that the molecular pathogenesis of this condition is mediated by type I IFN. It has also been shown that IFN-γ serum levels are increased in SLE patients, and in mouse models, the receptor of this cytokine was necessary to the disease development. The massive amount of circulating IFN correlates to disease severity, which is likely to be triggered by excessive pDC activation. Recently, clinical trials evaluating anti-IFN-α monoclonal antibodies for SLE have been conducted, exhibiting promising results. Moreover, a trial evaluating a monoclonal antibody that binds IFN-γ was conducted, but no significant improvements in the efficacy outcome measures were observed. Additionally, a recent study demonstrated that keratinocytes may participate on the pathophysiological of the cutaneous manifestation of the SLE, by increasing cell apoptosis and producing pro-inflammatory cytokines, especially IL-23, IL-12, IL-6, IL-17, (Th17-related cytokines), IL-10 and TFG-β [16, 30, 77, 78].
\nIn parallel, another autoimmune disease widely studied that involves cytokines, besides several other factors, is the type 1 diabetes mellitus. This disease is characterized by pancreatic β cells destruction, which it is due to hypersensitivity reactions mediated by CD4+ TH 1 cells reactive with islet antigens, the effect of cytotoxic T lymphocyte on lysis of islet cells, and local production of cytokines, especially TNF, IL-1, IL-21 and IFN-α. In some cases, the islets show cellular necrosis and lymphocytic infiltration, consisted of both CD4+ and CD8+ cells. Remaining islet cells often express class II MHC molecules, an effect of local production of INF-γ by the T cells [33, 73, 79]. The onset of young age of this disease may be associated with upregulation of growth factors, especially GM-CSF and IL-7. Other mediators overexpressed are the pro-inflammatory cytokine IL-1β, the regulatory cytokine IL-10, IL-27, and some Th17 cytokines (IL-17, IL-21, IL- 23). Additionally, patients that involve to ketoacidosis, a serious complication of the disease, have a tendency for higher IL-8 and IL-10 levels [80].
\nIn the same way, it stands out the rheumatoid arthritis, a chronic and systemic autoimmune disease described as a progressive disability on joints, particularly of the fingers, shoulders, elbows, knees and ankles that can promote systemic consequences like cardiovascular, pulmonary and skeletal disorders. It is characterized by the production of autoantibodies, like rheumatoid factor, cytokines, chemokines, hyperplasic synovium, osteoclastogensis and angiogenesis. The pro-inflammatory cytokines IL-1α/β, IL-8, IL-6, TNF-α, INF-y and some CSFs are responsible for the pathogenesis of this disease, and are involved with the intracellular molecular signaling pathway that causes chronic inflammation on synovial membrane. These cytokines, especially TNF-α, activates the leukocytes endothelial cells and synovial fibroblasts, and stimulates the production of collagenases that are responsible for the destruction of the cartilage, ligaments and tendons of the joints. Therefore, monoclonal antibody drugs, such as anti-TNF are approved for treatment of this disease [33, 75, 76, 81].
\nIt is also believed that bone destruction in rheumatoid arthritis is due to overexpression of the TNF family cytokine receptor activator of nuclear factor KB (RANK), an essential mediator that promotes maturation and activation of osteoclasts [33, 76]. Therefore, the cytokines on rheumatoid arthritis promote the autoimmunity, the destruction of joint tissue and maintain the synovial inflammation [82].
\nThe multiple sclerosis is a neurodegenerative autoimmune disease of high mortality in adults, characterized by a chronic inflammation in the central nervous system with secondary demyelination due to leukocyte and cytokines infiltration of brain tissue and spinal cord. Clinical manifestations are weakness, paralysis and ocular symptoms [33, 73]. A recent study proposed the role of Th1 lymphocytes in the pathogenesis of the brain inflammation, with several cytokines involvement. Th1 lymphocytes produces mainly IFNγ (type II IFN) that is responsible for the production of other pro-inflammatory cytokines, and chemoattractants, such as IL-2, IFNγ, CC chemokines, like CCL5, CCL11 and CCL27 and CXC chemokines, especially CXCL1 and CXCL10. On the other hand, lower levels of circulating type I IFN are observed. Therefore, unlike SLE, multiple sclerosis treatment involves the administration of IFN-β. Additionally, an upregulation of CCL27 was found in cerebrospinal fluid of multiple sclerosis patients, demonstrating the possibility of its involvement on activation and migration of autoreactive immune effectors in the brain, and consequently a potential contribution for the pathogenesis of this disease [83].
\nVitiligo, is another autoimmune disease, characterized by the skin depigmentation, which is associated to the production of antibodies against the melanocytes, and it is more frequent in patients that have other autoimmune diseases, like Grave’s disease [73]. A variety of cytokines are increased in vitiligo patients in relation to healthy people. A recent systematic review demonstrated an association between the expression of some kind of cytokines in vitiligo skin, especially INF-y, TGF-β, IL-1β, IL-17, and the chemokines CXCL9, CXCL10 and CXCL12. IFN-y and IL-1β are closely related to the pathogenesis of vitiligo, but serum TGF-β and IL-17 are more abundantly expressed in relation to the others [84].
\nFinally, another disease that has the participation of cytokines on its pathogenesis is the heart failure, a chronic disease characterized by a cardiac impairment due to hypertension, myocardial infarction, arrhythmias and other heart diseases. A recent evidence showed the involvement of the adaptive immune system in the development and progression of heart failure, which is related to high mortality in adults. T cells, particularly TH1, and TH17 and B1 lymphocyte, contribute to the pathologic chronic inflammation, and cell migration. The inflammatory component of this disease, which has a closely relation to the morbidity and mortality, are the cytokines, including TNF-α, TNF-β, IL-1, IL-6, IL-7, IL-10 and IFN-y, chemokines and cardiac autoantibodies. Those factors are associated with cardiomyocyte death and tissue remodeling by fibrosis, contributing to the left ventricle dysfunction, and consequently to disease progression. In detail, initially the dendritic cells and other antigen-presenting cells can process specific proteins of the myocardial tissue and theirs contact with memory B cells promotes the release of autoantibodies, and consequently activates pro-apoptotic pathways, by antigen-dependent cell cytotoxicity, and complement-mediated cell cytotoxicity in health myocytes. Another characteristic of the pathogenesis of heart disease is the production of inflammatory mediators by B cells, such pro-inflammatory cytokines (TNF-α and IL-6) and chemokines, which recruit monocytes involved with inflammation and heart remodeling, beyond the activation of T lymphocytes, leading to the production of other specific inflammatory cytokines (IFN-y and IL-2) [73, 85].
\nSelective immunosuppression of B-lymphocytes may be a promising therapeutic on acute and chronic heart failure, as the blockage of the immune mediators, such cytokines, once they are involved to the propagation of the disease [85].
\nIn sum, different kinds of cytokines are involved on autoimmune diseases, which plays an important role especially on inflammatory process, and contributing to the pathogenesis, in most cases. Studies have been performed, in order to establish the association between cytokines and the evaluation of these diseases, with the objective of developing therapeutic strategies, such as anti-TNF for rheumatoid arthritis.
\nIn this chapter, the main aspects regarding the different types of cytokines and their main functions were reviewed. Hence, the comprehensive and fundamental role of cytokines in the immune system could be thoroughly investigated. Additionally, the contribution of these molecules to the development of diseases, particularly related to autoimmunity, as well as its use as treatment approach for some clinical conditions was explored.
\nThe Edited Volume, also known as the IntechOpen Book, is an IntechOpen pioneered publishing product. Edited Volumes make up the core of our business - and as pioneers and developers of this Open Access book publishing format, we have helped change the way scholars and scientists publish their scientific papers - as scientific chapters.
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\n\nCURRENT PROJECTS
\n\nTo view current Open Access book projects that are Open for Submissions visit us here.
\n\nNot sure if this is the right publishing option for you? Feel free to contact us at book.department@intechopen.com.
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