Immunology is a source of continuous discoveries; Immunology was and still is a source of continuous discoveries. Immunomodulation encompasses all therapeutic interventions aimed at modifying the immune response. Immunostimulation is desirable to prevent infection in states of immunodeficiency and to fight infections and cancer. On the other hand, immunosuppressive agents inhibit the activity of the immune system, and they are used to prevent the rejection of transplanted organs and tissues and to treat autoimmune diseases or diseases that are most likely of autoimmune origin (e.g., rheumatoid arthritis, systemic lupus erythematosus, Crohn’s disease, ulcerative colitis, etc.), or other nonautoimmune inflammatory diseases (e.g., allergic asthma). The discovery of immunomodulatory agents from medicinal plants devoid of toxic side effects, with enhanced bioavailability and that can be used for a long duration, is of great actuality. Research on natural immunomodulators provides a therapeutic solution that addresses a multitude of disorders. Plant phenolic compounds already proved beneficial effects in cardiovascular diseases, diabetes, and cancer, exerting mainly antioxidant and anti-inflammatory effects. The concepts of “immunomodulatory,” “anti-inflammatory,” and “antioxidant” are often strongly related, and a review of phenolic compound action on immune system should be analyzed in a context, revealing their mechanism of action on effector cells and also on the system as a whole.
- phenolic compounds
Immune response is one of the most complex mechanisms of the living body, involving the strong cooperation of a large variety of cell types for defending against any potential dangerous agent. Perturbation of this well-adapted process results in a cascade of disorders and even the occurrence of chronic diseases, making the regulation of the immune system a key factor in maintaining a healthy equilibrium of the body. The discovery of immunomodulatory agents from medicinal plants devoid of toxic side effects, with enhanced bioavailability and that can be used for a long duration, is of great actuality.
In terms of molecular weight, phytocompounds are classified in high-molecular compounds such are peptides, polysaccharides, and low-molecular compounds—terpenes, alkaloids, and also phenolics. Plant phenolic compounds already proved beneficial effects in cardiovascular diseases, diabetes, and cancer, exerting mainly antioxidant and anti-inflammatory effects. Most of the plant-derived phenolics influence the nonspecific immune response mainly by enhancing phagocytosis and proliferation of macrophages and neutrophils. The concepts of “immunomodulatory,” “anti-inflammatory,” and “antioxidant” are often strongly related, and a review of phenolic compounds action on immune system should be analyzed in a context, revealing their mechanism of action on effector cells and also on the system as a whole.
2. Overview on the immune system
Immune response is controlled both by direct interaction of different types of cells (lymphoid cells: B and T lymphocytes, T helper (Th) cells, natural killer (NK) cells; myeloid cells: neutrophils, basophils, monocytes, macrophages) and by-products of synthesis they secrete (immunoglobulins, cytokines: interleukines, colony-stimulating factors, growth factors, interferons, etc).
Although innate and adaptive immunities work complementarily to provide an overall protection to the human body, they appeared at different times in evolution. Basic mechanisms of the innate immunity are found both in vertebrates and invertebrates and even in plants, while adaptive immune response is specific to vertebrates .
Innate immunity has no capacity for immunological memory and employs an antigen-independent defense mechanism that provides host defense immediately or within hours after exposure to pathogens. Cells involved in this response comprise phagocytic cells (neutrophils, monocytes, and macrophages), cells secreting inflammatory mediators (basophils, mast cells, and eosinophils), and natural killer (NK) cells. Pathogen-associated molecules (called pathogen-associated immunostimulants) stimulate two types of innate immune responses—inflammatory responses and phagocytosis by cells such as neutrophils and macrophages , processes regulated by soluble mediators known as cytokines. The mechanism is complex, and a precise delimitation of immunity, inflammation, and oxidation cannot be set. Innate immunity can also stimulate adaptive immune response with the help of a group of specialized cells known as antigen-presenting cells (APCs) such are dendritic cells (DCs). APCs display the processed antigen to lymphocytes and collaborate with them to elicit the immune response. Unlike innate immunity, the adaptive immune response involves antigen-specific antibodies, and a certain time interval is required for the maximal response to be achieved after exposure to the antigen.
Adaptive responses are mainly conducted by T cells, facilitated by APCs in cell-mediated immunity and B cells in antibody-mediated immunity. The T lymphocyte group represents 60–80% of total lymphocytes and has a very high lifetime and is mainly involved in eradication of intracellular pathogens by activating macrophages and by killing virally infected cells. These lymphocytes recognize the primary structure of an antigen, a mechanism different from that of B lymphocytes and plasma cells, which recognize the antigen by the spatial structure. T helper (Th) lymphocytes represent 2/3 of total lymphocytes and are of special importance because they secrete interleukins, messenger molecules that facilitate the communications between immune system cells. Depending on the type of cytokines that they secrete, Th1 cells producing interleukin-2, IFN-γ, and TNF-α and triggering inflammatory reactions and Th2 cells producing interleukins 3, 4, and 5, the main stimulator of immunoglobulin A and E synthesis, are distinguished .
In antibody-mediated immunity, activation of B lymphocytes conducts to plasma cells synthesizing immunoglobulins or memory B cells leading to immunological memory.
3. Overview on phytophenols
Phytophenols are secondary metabolites based on a common carbon skeleton structure—the C6–C3 phenylpropanoid unit . Among this group, several classes are described:
Most of the compounds are hydroxylated on A ring, at C5 and C7 positions. On the ring B are grafted 1–3 phenolic groups at C4′, 3′, and 5′. Depending on the degree of oxidation and substituent type of segment, several classes are classified:
Flavones—double bond between C2 and C3 (e.g., apigenin, luteolin)
Flavonols—flavones 3-hydroxylated (e.g., kaempferol, galangin, quercetin, miricetin)
Flavanones—flavones 2,3-dihydrogenated (e.g., naringenin, hesperetin)
Flavanonols—flavonols 2,3-dihydrogenated (e.g., taxifolin, dihidrokaempferol) 
Also, other varieties of flavonoids are:
Biflavonoids are dimer of flavonoids. The monomers are linked in positions 6 and 8, which are highly reactive. The links established can be C–C (amentoflavone, bilobetol, ginkgetol) or C–O–C (hinokiflavona). The hydroxyl groups may be free or, most often, methylated.
Isoflavones are 3-phenylbenzo-γ-pyrone derivatives (3-phenylchromone), specific for Fabaceae family (species of this family contain a specialized enzyme responsible for converting 2-phenylchromane to 3-phenylchromane). Isoflavones are usually found in free state (daidzein, genistein) and very rare as heterosides (mainly O-heterosides) (daidzein, puerarin) .
Chalcones (1,3-diaryl-2-propen-1-ones) are α,β-unsaturated ketones, comprised of two aromatic rings, that function as precursors in the synthesis of flavonoids and isoflavonoids (phloretin, arbutin).
In regard to
4. Aspects related to the structure-activity relation of phytophenols
It was showed that there are differences in immunomodulation exerted by flavonoid glycosides and their corresponding aglycones. While quercetin is able to activate concomitantly lymphocytes and secretion of IFN-c, the similar flavonoid rutin (quercetin-3-rutinoside) significantly stimulates the secretion of IFN-c, but do not elevate the proliferation of human peripheral blood mononuclear cells (PBMC), indicating the sugar moiety as the key point for different responses .
The importance of the sugar at position 3 for the selective immunosuppression by astilbin (taxifolin 3-rhamnoside) was highlighted by Guo et al. Most of the flavonoid glycosides have glucose attached to aglycones and are usually hydrolyzed by glucosidase. In the case of astilbin, the sugar attached to aglycone is rhamnose, which is likely difficult to hydrolyze, and it is suggested that this phytocompound may show a different metabolic route from other flavonoids, owing to the type and position of sugar attached [13, 14].
Hydroxylations of flavonoids at positions 5 and 7, together with the double bond at C2–C3 and the position of the B ring at 2, appear to be associated to the highest inhibition of pro-inflammatory cytokine expression . Luteolin and apigenin contain hydroxyl groups in their backbone, and it was suggested that these may be involved in immunomodulatory activities since luteolin, which contains hydroxyl groups both at the 3′ and 4′ positions in ring B, exhibits stronger immunomodulatory properties than apigenin that has only a 4′ hydroxyl group in ring B . For chalcone class, trimethoxy chalcones at the A ring with fluoro, chloro, and bromo substitution in the B ring, like 2′-hydroxy-3-bromo-6′-methoxychalcone, 2′-methoxy-3,4-dichlorochalcone, flavokawain A, or flavokawain B, are considered better inhibitors of NF-κB . The number and position of methoxy group seems to be correlated to immunomodulatory capacity as in the case of coumarins. For instance, two methoxy groups (isopimpinellin) are correlated to lymphocyte activation, while one methoxy group (xanthotoxin) conducts to IFN secretion; bergapten (5-methoxypsoralen) is a better IFN-γ activator than xanthotoxin (8-methoxypsoralen) .
Due to the fact that the immune response is very complex, some studies were focused on anti-oxidative immune-mediated mechanisms, and it was shown that the most important feature is the presence of a C–2,3 double bond in combination with a 4-oxo group as it is proved by the higher antioxidant activity of luteolin comparing to apigenin . Souza et al.  showed that flavonoid aglycones have high-antioxidant inhibitory activities, while C-glycosylated flavonoids have no significant effect even at the highest concentration tested (50 μmol/L).
Another factor that appears to be important for the influence on the immune response, in particular stimulation of T-cell cytokine production by polyphenols, is the size of the polyphenol molecule [19, 20]. Schepetkin et al.  showed that molecular subunits of oenothein B with smaller molecular weights do not have the same leukocyte immunomodulatory capacity, and also procyanidin oligomers, but not monomers, are able to stimulate innate lymphocytes . Also, the chain length of flavanol fractions has a significant effect on cytokine release from both unstimulated and LPS-stimulated PBMCs. Long-chain flavanol fraction and short-chain flavanol fraction, in the absence of LPS, stimulated the production of GM-CSF and increase expression of the B-cell markers CD69 and CD83. The oligomers are potent stimulators of both the innate immune system and early events in adaptive immunity .
5. Aspects related to phytophenol bioavailability
Research regarding bioavailability of phytophenols is essential for the establishment of dietary management of diseases . Increased intake of flavonoids with higher in vitro activity is not a guaranty for a strong pharmacological effect in vivo because low absorption and rapid elimination cause a limited bioavailability. In most of the published data regarding this issue, the concentration of polyphenols in blood and urine after ingestion of phenols rich food was measured as an indicator of their absorption , but there are complex reactions of metabolization hindering the biological activity of the parent compounds . Many of these phytophenols with high activity in vitro are not object of industrial investment because of their oral bioavailability below 30% .
The absorption of some, but not all, dietary polyphenols occurs in the small intestine. Before the absorption, these compounds must be hydrolyzed by intestinal enzymes. It is believed that the phenolic compounds are absorbed by a passive diffusion mechanism (aglycones) or by carriers present in the intestine . Polyphenols that are not absorbed in the small intestine reach the colon, where they undergo substantial structural modifications by colonic microflora that hydrolyzes glycosides into aglycones and degrades them to simple phenolic acids . Once absorbed, and prior to the passage into the bloodstream, the polyphenol-derived aglycones undergo other structural modifications due to the conjugation process . Glucuronidation and sulfation conjugation reactions are described to have a significant impact on the bioactivity of polyphenols. In particular, the low oral bioavailability of some phenolic substances could be explained by glucuronidation . The low absorption profile of curcumin was demonstrated in human and rat models , and it was attributed not only to the poor solubility of this compound but also to the glucuronidation or sulfation processes.
These conjugation reactions significantly reduce the polyphenol antioxidant activity, since both sulfation and glucuronidation occur at the reducing hydroxyl groups in the phenolic structure. It was already shown that these groups are mainly responsible for the antioxidant and immunomodulatory properties of polyphenols . Nevertheless, conjugation reactions might enhance certain specific bioactivities. For example, Koga  described that the plasma metabolites of catechin have an inhibitory effect on monocyte adhesion to interleukin-1 in beta-stimulated human aortic endothelial cells, while catechin had no effect . Lignans, for example, need to be biotransformed by gut microflora to be biologically active .
Manach et al.  suggested that among the most well-absorbed phytophenols in humans are gallic acid and isoflavones, catechins, flavanones, and quercetin glucosides, while the least well-absorbed are proanthocyanidins, the galloylated tea catechins, and the anthocyanins.
The efficiency of absorption of phenolic acids is markedly reduced when they are present in the esterified form rather than in the free forms as it was observed in patients with colonic ablation where caffeic acid was better absorbed than chlorogenic acid . Moreover, it was shown that the occurrence of ferulic acid and antioxidant activity in plasma is increased following intake of food matrix with ferulic acid bound to arabinoxylans compared with results after intake of free ferulic acid, proving that the action of gut microbiota may lead to improved bioavailability .
6. Interaction of phytophenols with the immune system
6.1. Dendritic cells
Dendritic cells (DCs), as essential component of the innate immune system, are the most potent antigen-presenting cells (APCs), allowing the critical decision between immune activation and tolerance. Aberrant activation of DCs can cause detrimental immune responses; thus, agents effectively modulating their functions are of great clinical value. Several plant phenolic compounds proved their ability to influence DC function, especially in a suppressive way. Because Th1 cells are either functionally immunogenic or provide protection against invading pathogens, the inhibition of DC-mediated Th1 polarization may constitute an associated immunosuppressive mechanism .
Similar modes of action were established for daidzein (isoflavone) , silibinin (flavonolignan) , fisetin (flavonol) , apigenin , and baicalin (flavone glycoside)  in LPS-stimulated DCs, all compounds exhibiting immunosuppressive activity by inhibiting cell maturation and activation. They significantly and dose-dependently inhibit the expression levels of maturation-associated cell surface markers including CD40, costimulatory molecules (CD80, CD86), and major histocompatibility complex class II (I-A(b)) molecule. An impaired induction of the T helper type 1 immune response and a normal cell-mediated immune response induced by the abovementioned compounds were noticed as it was previously found in the case of curcumin . This well-known phytophenol is also a potential therapeutic adjuvant for DC-related acute and chronic diseases being highly efficient at Ag capture, via mannose receptor-mediated endocytosis . The suppressive effect on DCs was also showed for another phenolic compound belonging to ellagitannins class, oenothein B; it was associated with the induction of apoptosis without the activation of caspase-3/7, 8, and 9; and this was supported by the morphological features indicating significant nuclear condensation .
Stimulation of cell-mediated immune response is one of the most studied effects of plant phenolic compounds, the experiments being carried out both in vitro and in vivo on different species: humans, fish, bovine, etc. In this respect, it was showed that oenothein B, a polyphenol isolated from
Stimulation of both humoral and cell-mediated seroresponse was observed (increases of the antibody titers, lymphocyte, and macrophage cells) also in chicks, after administration of an 80% aqueous methanol extract from the leaves of
In healthy well-nourished humans, it was showed that consumption within the usual daily intake range of orange juice and its major polyphenol hesperidin (daily 500 mL of orange juice or an isocaloric control beverage with hesperidin (292 mg in a capsule) for 3 weeks) do not induce immunomodulation of cell immune function .
Differences between cell-mediated immune response modulations of different compounds belonging to the same class were found in the case of isoflavones.
Daidzein potentiates proliferation of mixed splenocyte cultures activated with ConA or LPS and the secretion of interleukins 2 and 3, while genistein have no influence, although a significant cooperation between these compounds may occur . Contradictory findings regarding genistein (25, 250, 1250 ppm) were presented by Guo et al. , which showed that exposure to genistein increases the number of splenic B cells (L), macrophages (L and M), T cells (H), T helper cells (L and H), and cytotoxic T cells (M and H). It was suggested that genistein may modulate the immune system by functioning as either an estrogen agonist or antagonist. The differential effects of genistein on thymocytes in F(1) male and female mice indicate that genistein immunomodulation might be related to its effect on thymus .
6.2.1. B cells
Several studies show that epigallocatechin gallate (EGCG) enhances the mitogenic activity of B lymphocytes but not T lymphocytes. Gallic acid and tannic acid induced some enhancement, but rutin, pyrogallol, and caffeine did not, indicating that the galloyl group on EGCG was responsible for enhancement .
Cumella et al.  found that quercetin, but not taxifolin (dihydroquercetin), inhibited mitogen-stimulated immunoglobulin secretion of IgG, IgM, and IgA isotypes in vitro with an IC50 of approximately 30 mM for each isotype.
6.2.2. T cells
These cells express TCR on their surface to recognize specific antigens processed by APCs, such as dendritic cells, macrophages, and fibroblasts. Activated T cells differentiate into either cytotoxic T cells (CD8+ cells) or Th cells (CD4+). Cytotoxic T cells participate in the destruction of infected cells by secreting perforin, granzyme, and granulysin. Th cells have no direct killing activity in the infected cells but direct other immune cells to act against pathogen-infected cells, mainly by secreting several cytokines. After infection with a certain pathogen, the immune system must select the best defense mechanism, which involves the differentiation of Th cells into Th1 (to promote the bactericidal activities of macrophages) and Th2 cells (to activate or recruit IgE-producing B cells, mast cells, and eosinophils).
Intake of representative polyphenols (flavones, flavone-3-ols, catechins, antocyanidins, flavanones, procyanidins, and resveratrol) can improve a skewed Th1/Th2 balance and suppress antigen-specific IgE antibody formation . This was suggested as one mechanism of action of quercetin contributing to its anti-inflammatory and immunomodulating properties having potential of being utilized in several types of allergic reactions. Quercetin is able to inhibit IL-6 and IL-8 better than cromolyn (antiallergic drug disodium cromoglycate) , and it ameliorates experimental autoimmune encephalomyelitis, which is associated with Th1-mediated immune responses .
A preventive effect on IgE synthesis mediated by Th2 cells was suggested for cocoa. On the other hand, cocoa intake modifies the functionality of gut-associated lymphoid tissue by means of modulating IgA secretion and intestinal microbiota .
In allergic diseases, besides the influence on Th2 activation, regulatory T cells represent another possible target for polyphenols activity .
Jaceosidin, a flavone isolated from
Kawamoto et al. showed that 6-gingerol suppresses the expression of Th1 cytokines even in strong Th1-polarizing conditions in vitro and also the expression of Th2 cytokines due not to enhancement of Th1 cytokine production but to inhibition of the general pathway for cytokine expression. Another phenolic phytocompounds that contribute to Th1 polarization of the immune response are procyanidin C1  and proanthocyanidin 1 .
An immune shift from Th1 to Th2 is suggested for tea polyphenols taking into consideration increased serum concentrations of anti-inflammatory cytokine, such as IL-4. A T lymphocyte transformation test (LTT) demonstrated that dietary tea polyphenols promote the proliferation and activation of T lymphocytes, reflected by elevation of CD4+/CD8+ ratio, inhibition of pro-inflammatory IL-1, and IFNγ expression caused by oxidative stress . Also, umbelliprenin (UMB) and methyl galbanate (MG), terpenoid coumarins isolated from
The mechanism of decreasing the activity of effector Th1 cells proposed for cirsilineol (a trimethoxyflavone isolated from
Besides the cytotoxic T cells and Th cells mentioned above, there are the regulatory T (Treg) cells, which are critical in maintaining immune tolerance and suppressing autoimmunity. Green tea and its active ingredient, epigallocatechin-3-gallate (EGCG), have been shown to improve symptoms and reduce the pathology in some animal models of autoimmune diseases. Mice treated with EGCG had significantly increased Treg frequencies and numbers in the spleen and lymph nodes and had inhibited T-cell response [66, 67] and dose-dependently attenuated the disease’s severity .
Macrophages are the main cells responsible for the innate immunity, and their activation by lipopolysaccharide (LPS) from Gram-negative bacteria or IFNγ from host immune cells is important for controlling infections. Activation of mononuclear cells and increase of the phagocytic response are induced by several phytophenols, mainly via influencing of MAPK and nuclear factor κB (NF-κB) signaling pathways: daidzein at high doses (20 and 40 mg/kg) , coumarin (1,2-benzopyrone) , procyanidin A1 , procyanidin C1 (max dose 62.5 μg/ml) and procyanidin dimer B2 , kaempferitrin from
As macrophages are stimulated to secrete a battery of inflammatory mediators and cytokines, regulation of their activity ensures an appropriate immune response. Inappropriate or prolonged macrophage activation is largely responsible for various inflammatory states. There are also phytophenols that inhibit the secretion of various pro-inflammatory molecules from macrophages or their migration: grape polyphenols , cianidol , EGCG , fisetin , quercetin, kaempferol, daidzein, genistein , xanthohumol , etc.
Orange juice and hesperidin, a flavanone glycoside contained in the juice, showed different immune responses, suggesting that hesperidin displays a suppressive effect on inflammation generated by LPS, while the juice seems to enhance the functions of macrophages associated with antimicrobial activity .
These cells provide rapid response and nonspecific protective effect against invading pathogens, and the exposure of antigen by APCs is not required to activate these cells . Most of the effects exerted by phytophenols on neutrophils are based on inhibition of superoxide anion production: biflavonoids like procyanidin, fukugetin, amentoflavone, and podocarpusflavone isolated from
The effects of flavonoids on human neutrophils are complex and suggest several sites of action depending upon the flavonoid’s subcellular distribution and pathway of stimulation .
6.5. Modulation of soluble factor secretion
Humoral immunity is mostly quantified by serum levels of specific immunoglobulins. A stimulatory effect on IgM- and IgG-mediated humoral immune response was observed in the case of green tea, a well-known rich source of polyphenols . Serum IgM and IgG levels are also significantly increased, whereas specific IgA and IgE are not changed after ellagic acid (a natural phenolic compound found in fruits and nuts) treatment .
IgG response is increased after treatment with pomegranate extract rich in polyphenols (16.9% gallic acid equivalent (GAE) per day in calves)  and red wine (Negroamaro) pretreatment of lymphomonocytes . Immunoglobulin synthesis is induced also by cianidol , its O-methyl-derivative  and daidzein .
Humoral immunity measured by anticomplement activity showed an increase in inhibition of the complement system after the addition of morin (natural flavonoid that is the primary bioactive constituent of the family Moraceae) hydrate (significant effect at 15 μM concentration) .
Catechin, epigallocatechin gallate (EGCG), epicatechin (EC), luteolin, chrysin, quercetin, and galangin increase IL-2 secretion, while EGC, apigenin, and fisetin inhibit the secretion. There was no obvious structure-activity relationship with regard to the chemical composition of the flavonoids and their cell biological effects . Contradictory results were obtained by Xiao et al. , which reported the inhibitory action of chrysin on splenic mononuclear cell secretion of interleukin-2, after oral administration of the phytocompound from day 1 to day 16 (50 mg/kg once daily), while, for therapeutic treatment, rats received chrysin from day 7 to day 16 at the same dose once daily).
Inhibitory effects on IL-2 production have also equol (4′,7-isoflavandiol) , quercetin by IL-2R alpha-dependent mechanism  and curcumin, which inhibits IL-2 synthesis in ConA, PHA, and PMA stimulated SP-L in a concentration-dependent manner with an ED50 measured at 3.5 μg/ml. Exogenous IL-2-stimulated SP-L proliferation is also inhibited by curcumin in a concentration-dependent manner with an ED50 of 2 μg/ml . 8-Methoxypsoralen (140 μM) induces a dose-dependent decrease in IL-2 receptor expression on PHA-stimulated lymphocytes, explaining the mechanism by which this compound impairs lymphocyte function, since IL-2 receptors play a central role in lymphocyte proliferation and immune reactivity [92, 93].
IL-12 is the most important factor driving Th 1 immune responses. An interesting dynamic was showed in the case of the orange juice and its main component, hesperidin. In non-LPS-stimulated macrophages, IL-12 level was increased by orange juice by 143% and hesperidin by 72%. For LPS-stimulated macrophages, the orange juice treatment did not alter IL-12 level, while hesperidin treatment decreased IL-12 level by 29%, suggesting that hesperidin displays a suppressive effect on inflammation generated by LPS . Curcumin exhibits impaired IL-12 expression in DCs ; quercetin blocks IL-12-dependent JAK-STAT signaling in Th cells ; ellagic acid reduces IL-12 production both ex vivo and in vivo treatment ; chrysin , licochalcone E , xanthohumol, shows the strongest inhibitory effect on IL-12 production in LPS-stimulated xanthohumol 4’-O-beta-D-glucopyranoside (XNG) being less effective, followed by isoxanthohumol and 8-prenylnaringenin while (2S)-5-methoxy-8-prenylnaringenin 7-O-beta-D-glucopyranoside have no effect . macrophages, xanthohumol 4′-O-beta-D-glucopyranoside (XNG) being less effective, followed by isoxanthohumol and 8-prenylnaringenin, while (2S)-5-methoxy-8-prenylnaringenin 7-O-beta-D-glucopyranoside  and licochalcone E have no effect .
Inhibitory effect on IL-1b secretion has apigenin  and flavokawain A in the LPS-stimulated cells ; curcumin in DCs ; curculigoside in B16F10-induced metastatic tumor progression in experimental animals ; ellagic acid in ex vivo and in vivo experiments ; chrysin, in splenic mononuclear cells ; equol (4′,7-isoflavandiol) ; and kurarinone and kuraridin in RAW264.7 macrophages . There are also phenolic phytocompounds, which promote pro-inflammatory IL-1b secretion: oenothein B , polyphenols contained in red wine (Negroamaro) , and 1% dietary EGCG .
Quercetin , 6-gingerol , and ellagic acid  suppress interleukin IL-4 production, one of the key cytokines secreted by Th2 cells.
Suppression of LPS-induced expression of pro-inflammatory cytokine IL-6 is induced by licorice flavonoids ; 1% dietary EGCG ; flavokawain A ; curcumin ; quercetin attenuates TLR7-induced expression, effect of mediated by HO-1 ; curculigoside ; syringic acid or vanillic acid ; licochalcone A ; chrysin ; apigenin, through modulating multiple intracellular signaling pathways in macrophages and prevents LPS-induced IL-6 production by reducing the mRNA stability via inhibiting ERK1/2 activation ; and luteolin at transcriptional level .
It is well known that IL-17 is an essential factor involved in autoimmune diseases, and some synthetic inhibitors are already in clinical testing. As regards phytophenols, grape seed proanthocyanidin extract (GSPE) shows promising results, attenuating clinical symptoms in a model of collagen-induced arthritis in mice .
Based on the inhibitory effect on TNF-α secreted by LPS-stimulated cells, flavonoids were classified in four groups: strong (flavones, flavonols, chalcones), moderate (flavanones, naringenin, antocyanidin, pelargonidin), weak (genistein), and inactive (eriodictyol) . Several phenolic phytocompounds successfully suppress the expression of pro-inflammatory cytokines such as TNF-α; flavokawain A ; curcumin ; quercetin ; curculigoside ; ellagic acid ; syringic and vanillic acids ; apigenin ; chrysin ; kurarinone and kuraridin ; luteolin ; equol (4′,7-isoflavandiol) ; and cardamonin, a chalcone derivative isolated from
Chrysin inhibited the splenic mononuclear cell secretion of IFNγ ; quercetin is suggested to exert T-bet-dependent IFNγ suppression , ellagic acid , syringic and vanillic acid , equol (4′,7-isoflavandiol) . On the other hand, other phytophenols enhance IFNγ level: curculigoside , oenothein B, by both bovine and human NK cells and T cells, alone and in combination with IL-18 , and a response not observed with other commonly studied polyphenols .
6.6. Influence on transcription factors
Nuclear factor κB (NF-κB) plays an important role in inflammatory processes, in autoimmune response, apoptosis, and cell proliferation, by regulating the genes involved in these processes. This factor is activated mainly under conditions of oxidative stress, under the action of various pathogenic stimuli (viruses and bacteria but also inflammatory cytokines). Because of its effects on vital biological processes, modulation of its activation pathway is of great therapeutic potential.
Curcumin inhibits PMA-stimulated NF-κB activation in lymphocytes by 24, 38, and 73%, respectively, at final concentrations of 2.5, 5, and 10 μg/ml, respectively , and fisetin also inhibits LPS-induced nuclear factor κB activation and JNK/Jun phosphorylation . In LPS-stimulated macrophages, activation of NF-κB that is inhibited was reported for caffeic acid phenethyl ester ; licochalcone E, a constituent of licorice ; luteolin ; kurarinone and kuraridin ; astragalin (kaempferol-3-O-glucoside) ; naringin ; nodakenin, a coumarin isolated from the roots of
It was found that both phenolic acids and other phenolic compounds found in free form in cereal grains are significant modulators of NF-κB activity, but only their combinatorial action gives the desirable effect. Although ferulic and p-coumaric acids alone are effective modulators of NF-κB activity, a mixture of ferulic, caffeic, p-coumaric, and sinapic acids in low concentrations has significant synergistic, enhanced, and additive effects on NF-κB activity .
Considerable attention is currently focused on the development of natural medicines with less or no side effects, maximum efficacy, and low cost. Plant phenolic compounds proved to be competitive candidates for therapy in several disorders, and some of them undergone clinical trials (e.g., quercetin, curcumin). Modulation of immune system is a challenge, due to complex mechanisms involved and to route of administration, knowing that most of the plant-derived compounds are given orally in the form of medicines or even as functional foods.
Several aspects resulted from reviewing the literature: plant extracts are not always well characterized or standardized, making difficult to assign the immunomodulatory effect to a single compound; high concentrations of phenolic compounds are used for in vitro studies, and substances that have proven effective on laboratory scale are often ineffective in clinical trials, often due to bioavailability aspects (as these compounds are an important part of the human diet). Up to now, few human trials were carried out, most of them being focused on proving only the antioxidant or anti-inflammatory effect. This review reveals that phenolic compounds are a rich source of valuable potential therapeutic agents for immune system modulation, but further work needs to be carried out in order to establish therapeutical doses, precise mechanism of action, and optimal ways of administration.
The work was supported by a grant of
Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Available from: http://www.ncbi.nlm.nih.gov/books/NBK21054/
Patwardhan B, Gautam M. Botanical immunodrugs: scope and opportunities. Drug Discov Today. 2005;10(7):495–502.
Seabra R, Andrade P, Valentão P, Fernandes E, Carvalho F, Bastos M. Molecules 2009 14:2209. Biomaterials from Aquatic and Terrestrial organisms; Fingerman M, Nagabhushanam R. Eds.; Enfield, NH, USA: Science Publishers, 2006. pp. 115–174.
Istudor V. Pharmacognosy, phytochemistry, phytotherapy, vol. I Glycosides and lipids. 1998. Ed, Bucuresti: Medicala.
Balasundram N, Sundram K, Samman S Phenolic compounds in plants and agri-industrial by-products: antioxidant activity, occurrence, and potential uses. Food Chem 2006;99:191–203. doi: 10.1016/j.foodchem.2005.07.042
Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004; 79(5):727–747.
Holderness J, Hedges J, Daughenbaugh K, Kimmel E, Graff J, Freedman B, Jutila M. Response of γδ T cells to plant-derived tannins. Crit Rev Immunol. 2008;28(5): 377–402.
Gross GG. From lignins to tannins: forty years of enzyme studies on the biosynthesis of phenolic compounds. Phytochemistry. 2008;69(18):3018–3031.
Prior RL, Wu X. Anthocyanins: structural characteristics that result in unique metabolic patterns and biological activities. Free Radic Res. 2006;40(10):1014–1028. [PubMed: 17015246]
Hayasaka Y, Waters EJ, Cheynier V, Herderich MJ, Vidal S. Characterization of proanthocyanidins in grape seeds using electrospray mass spectrometry. Rapid Commun Mass Spectrom. 2003;17(1):9–16. [PubMed: 12478550]
Pandey K., Rizvi S. Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longev 2009;2:270–278. doi: 10.4161/oxim.2.5.9498
Cherng JM, Chiang W, Chiang LC. Immunomodulatory activities of common vegetables and spices of Umbelliferae and its related coumarins and flavonoids. Food Chem 2008: 106:944–950.
Chen CY, Peng WH, Tsai KD, Hsu SL. Luteolin suppresses inflammation-associated gene expression by blocking NF-kappaB and AP-1 activation pathway in mouse alveolar macrophages. Life Sci. 2007;81(23–24):1602–1614. http://dx.doi.org/10.1016/j.lfs.2007.09.028
Guo J, Qian F, Li J, Xu Q, Chen T. Identification of a new metabolite of astilbin, 3-O-methylastilbin, and its immunosuppressive activity against contact dermatitis. Clin Chem. 2007;53:3: 465–471. doi: 10.1373/clinchem.2006.077297
Rice-Evans CA, Miller NJ, Paganga G. Structure-anti-oxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 1996;20:933–956.
Kilani-Jaziri S, Mustapha N, Mokdad-Bzeouich I, El Gueder D, Ghedira K, Ghedira-Chekir L. Flavones induce immunomodulatory and anti-inflammatory effects by activating cellular anti-oxidant activity: a structure-activity relationship study. Tumor Biol 2016;37:6571–6579.
Yadav V, Prasad S, Sung B, Aggarwal B. The role of chalcones in suppression of NF-κB-mediated inflammation and cancer. Int Immunopharmacol 2011;11:295–309.
Souza JG, Tomei RR, Kanashiro A, Kabeya LM, Azzolini AE, Dias DA, Salvador MJ, Lucisano-Valim YM. Ethanolic crude extract and flavonoids isolated from Alternanthera maritima: neutrophil chemiluminescence inhibition and free radical scavenging activity. Z Naturforsch C. 2007;62(5–6):339–347.
Schepetkin I, Kirpotina L, Jakiw L, Khlebnikov A, Blaskovich C, Jutila M, Quinn M. Immunomodulatory activity of oenothein B isolated from Epilobium angustifolium. J Immunol. 2009;183(10):6754–6766. DOI: 10.4049/jimmunol.0901827.
Schepetkin I, Ramstead A, Kirpotina L, Voyich J, Jutila M, Quinn M. Therapeutic potential of polyphenols from Epilobium angustifolium(Fireweed). Phytother Res. 2016. DOI: 10.1002/ptr.5648)
Kenny T, Keen C, Schmitz H, Gershwin M. Immune effects of cocoa procyanidin oligomers on peripheral blood mononuclear cells. Exp Biol Med (Maywood). 2007; 232(2):293–300.
Gonzalez-Gallego J, Garcia-Mediavilla V, Sanchez-Campos S, Tunon M. Fruit polyphenols, immunity and inflammation. Br J Nutr 2010:104:S15–S27.
del Cornò M, Scazzocchio B, Masella R, Gessani S. Regulation of dendritic cell function by dietary polyphenols. Crit Rev Food Sci Nutr, 2016; 56(5):737–747, DOI: 10.1080/10408398.2012.713046
Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med 2004;36:838–849.
Gao S, Basu S, Yang Z, Deb A, Hu M. Bioavailability challenges associated with development of saponins as therapeutic and chemopreventive agents. Curr Drug Targets, 2012; 13:1885–1899.
de Souza J; Casanova L; Costa S. Bioavailability of phenolic compounds: a major challenge for drug development?, Rev Fitos Rio de Janeiro. 2015;9(1):1–72.
Kay C. Aspects of anthocyanin absorption, metabolism, & pharmacokinetics in humans. Nutr Res Rev 2006;19:137–146.
Wu B, Kulkarni K, Basu S, Zhang S, Hu M. First-pass metabolism via UDP-glucuronosyltransferase:a barrier to oral bioavailability of phenolics. J Pharm Sci 2011;100:3655–3681.
Ireson CR, Jones DJL, Orr S, Coughtrie MWH, Boocock DJ, Williams ML, Farmer PB, Steward WP, Gescher AJ. Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol Biomark Prevent 2002;11:105–111.
Piazzon, A., Vrhovsek, U., Masuero, D., Mattivi, F., Mandoj, F., Nardini, M. Antioxidant activity of phenolic acids and their metabolites: synthesis and antioxidant properties of the sulfate derivatives of ferulic and caffeic acids and of the acyl glucuronide of ferulic acid. J Agric Food Chem 2012;60:12312–12323.
Koga T, Meydani M. Effect of plasma metabolites of (+)-catechin and quercetin on monocyte adhesion to human aortic endothelial cells. Am J Clin Nutr 2001;73:941–948.
Heleno S, Martins A, Queiroz M, Ferreira I. Bioactivity of phenolic acids: metabolites versus parent compounds: a review Food Chem 2015;173:501–513.
Manach C, Williamson G, Morand C, Scalbert A, Remesy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr. 2005;81(1supp):230S–242S.
Olthof MR, Hollman PC, Katan MB. Chlorogenic acid and caffeic acid are absorbed in humans. J Nutr, 2001;131:66–71.
Hole A, Grimmer S, Jensen M, Sahlstrøm S. Synergistic and suppressive effects of dietary phenolic acids and other phytochemicals from cereal extracts on nuclear factor kappa B activity. Food Chem 2012;133:969–977.
Yoon MS, Lee JS, Choi BM, Jeong YI, Lee CM, Park JH, Moon Y, Sung SC, Lee SK, Chang YH, Chung HY, Park YM. Apigenin Inhibits Immunostimulatory function of dendritic cells: implication of immunotherapeutic adjuvant. Mol Pharmacol 2006; 70:1033–1044. DOI:10.1124/mol.106.024547
Yum M, Jung M, Cho D, Kim T. Suppression of dendritic cells’ maturation and functions by daidzein, a phytoestrogen.Toxicol Appl Pharmacol. 2011;257(2):174–181. DOI: 10.1016/j.taap.2011.09.002.
Lee J, Kim S, Kim H, Lee T, Jeong Y, Lee C, Yoon M, Na Y, Suh D, Park N, Choi I, Kim G, Choi Y, Chung H, Park Y. Silibinin polarizes Th1/Th2 immune responses through the inhibition of immunostimulatory function of dendritic cells. J Cell Physiol. 2007;210(2): 385–397. DOI:10.1002/jcp.20852
Liu S, Lin C, Hung S, Chou J, Chi C, Fu S. Fisetin inhibits lipopolysaccharide-induced macrophage activation and dendritic cell maturation. J Agric Food Chem. 2010; 58(20):10831–10839. DOI: 10.1021/jf1017093
Kim M, Kim H, Park H, Kim D, Chung H, Lee J. Baicalin from Scutellaria baicalensisimpairs Th1 polarization through inhibition of dendritic cell maturation. J Pharmacol Sci. 2013;121(2):148–156. DOI:http://doi.org/10.1254/jphs.12200FP
Kim G, Kim K, Lee S, Yoon M, Lee H, Moon D, Lee C, Ahn S, Park Y, Park Y. Curcumin inhibits immunostimulatory function of dendritic cells: MAPKs and translocation of NF-kappa B as potential targets. J Immunol. 2005;174(12):8116–8124. DOI:10.4049/jimmunol.174.12.8116
Yoshimura M, Akiyama H, Kondo K, Sakata K, Matsuoka H, Amakura Y, Teshima R, Yoshida T. Immunological effects of oenothein B, an ellagitannin dimer, on dendritic cells. Int J Mol Sci. 2012;14(1):46–56. DOI: 10.3390/ijms14010046
Ramstead A, Schepetkin I, Quinn M, Jutila M. Oenothein B, a cyclic dimeric ellagitannin isolated from Epilobium angustifolium, enhances IFNγ production by lymphocytes. PLoS One. 2012;7(11):e50546. DOI: 10.1371/journal.pone.0050546
Ramstead A, Schepetkin I, Todd K, Loeffelholz J, Berardinelli J, Quinn M, Jutila M. Aging influences the response of T cells to stimulation by the ellagitannin, oenothein B. Int Immunopharmacol. 2015;26(2):367–377. DOI: 10.1016/j.intimp.2015.04.008
Awad E, Awaad A, Esteban M. Effects of dihydroquercetin obtained from deodar (Cedrus deodara) on immune status of gilthead seabream ( Sparus aurataL.). Fish Shellfish Immunol. 2015;43(1):43–50. DOI: 10.1016/j.fsi.2014.12.009
Abd-Alla H, Moharram F, Gaara A, El-Safty M. Phytoconstituents of Jatropha curcasL. leaves and their immunomodulatory activity on humoral and cell-mediated immune response in chicks. Z Naturforsch C. 2009;64(7–8):495–501. DOI:10.1515/znc-2009-7-805
Perche O, Vergnaud-Gauduchon J, Morand C, Dubray C, Mazur A, Vasson M. Orange juice and its major polyphenol hesperidin consumption do not induce immunomodulation in healthy well-nourished humans. Clin Nutr. 2014;33(1):130–135. DOI: 10.1016/j.clnu.2013.03.012
Wang W, Higuchi CM, Zhang R. Individual and combinatory effects of soy isoflavones on the in vitropotentiation of lymphocyte activation. Nutr Cancer. 1997;29(1):29–34. DOI: 10.1080/01635589709514598
Guo TL, White KL Jr, Brown RD, Delclos KB, Newbold RR, Weis C, Germolec DR, McCay JA. Genistein modulates splenic natural killer cell activity, antibody-forming cell response, and phenotypic marker expression in F(0) and F(1) generations of Sprague-Dawley rats. Toxicol Appl Pharmacol. 2002;181(3):219–227. DOI:10.1006/taap.2002.9418
Guo TL, Chi RP, Zhang XL, Musgrove DL, Weis C, Germolec DR, White KL Jr. Modulation of immune response following dietary genistein exposure in F0 and F1 generations of C57BL/6 mice: evidence of thymic regulation. Food Chem Toxicol. 2006; 44(3):316–325. DOI:http://dx.doi.org/10.1016/j.fct.2005.08.001
Hu ZQ, Toda M, Okubo S, Hara Y, Shimamura T. Mitogenic activity of (−)epigallocatechin gallate on B-cells and investigation of its structure-function relationship. Int J Immunopharmacol. 1992;14(8):1399–1407.
Cumella JC, Faden H and Middleton E. Selective activity of plant flavonoids on neutrophil chemiluminescence (CL). J Allergy Clin Immunol 1987;77:131.
Kumazawa Y, Takimoto H, Matsumoto T, Kawaguchi K. Potential use of dietary natural products, especially polyphenols, for improving type-1 allergic symptoms. Curr Pharm Des. 2014;20(6):857–863. DOI:10.2174/138161282006140220120344
Mlcek J, Jurikova T, Skrovankova S, Sochor J. Quercetin and its anti-allergic immune response. Molecules. 2016;21(5).pii: E623. DOI: 10.3390/molecules21050623
Yu ES, Min HJ, An SY, Won HY, Hong JH, Hwang ES. Regulatory mechanisms of IL-2 and IFNgamma suppression by quercetin in T helper cells. Biochem Pharmacol. 2008;6(1):70–78. DOI:10.1016/j.bcp.2008.03.020
Pérez-Cano F, Massot-Cladera M, Franch A, Castellote C, Castell M. The effects of cocoa on the immune system. Front Pharmacol. 2013;4;4:71. DOI: 10.3389/fphar.2013.00071
Magrone T, Tafaro A, Jirillo F, Amati L, Jirillo E, Covelli V. Elicitation of immune responsiveness against antigenic challenge in age-related diseases: effects of red wine polyphenols. Curr Pharm Des. 2008;14(26):2749–2757. DOI:10.2174/138161208786264043
Yin Y, Sun Y, Gu L, Zheng W, Gong F, Wu X, Shen Y, Xu Q. Jaceosidin inhibits contact hypersensitivity in mice via down-regulating IFN-γ/STAT1/T-bet signaling in T cells. Eur J Pharmacol. 2011;651(1–3):205–211. DOI: 10.1016/j.ejphar.2010.10.068
Fang F, Tang Y, Gao Z, Xu Q. A novel regulatory mechanism of naringenin through inhibition of T lymphocyte function in contact hypersensitivity suppression. Biochem Biophys Res Commun. 2010;25;397(2):163–169. DOI: 10.1016/j.bbrc.2010.05.065
Sung NY, Yang MS, Song DS, Byun EB, Kim JK, Park JH, Song BS, Lee JW, Park SH, Park HJ, Byun MW, Byun EH, Kim JH. The procyanidin trimer C1 induces macrophage activation via NF-κB and MAPK pathways, leading to Th1 polarization in murine splenocytes. Eur J Pharmacol. 2013;714(1–3):218–228. DOI: 10.1016/j.ejphar.2013.02.059
Deng Q, Xu J, Yu B, He J, Zhang K, Ding X, Chen D. Effect of dietary tea polyphenols on growth performance and cell-mediated immune response of post-weaning piglets under oxidative stress. Arch Anim Nutr. 2010;64(1):12–21. DOI: 10.1080/17450390903169138
Zamani Taghizadeh RS, Iranshahi M, Mahmoudi M. In vitroanti-inflammatory and immunomodulatory properties of umbelliprenin and methyl galbanate. J Immunotoxicol. 2016;13(2):209–216. DOI: 10.3109/1547691X.2015.1043606
Niu X, Huang Z, Zhang L, Ren X, Wang J. Auraptene has the inhibitory property on murine T lymphocyte activation. Eur J Pharmacol 2015;750:8–13. DOI: 10.1016/j.ejphar.2015.01.017
Ranjan D, Chen C, Johnston T, Jeon H, Nagabhushan M. Curcumin inhibits mitogen stimulated lymphocyte proliferation, NFκB activation, and IL-2 signaling. J Surg Res. 2004;121(2):171–177. DOI: http://dx.doi.org/10.1016/j.jss.2004.04.004
Sun Y, Wu X, Yin Y, Gong F, Shen Y, Cai T, Zhou X, Wu X, Xu Q. Novel immunomodulatory properties of cirsilineol through selective inhibition of IFN-gamma signaling in a murine model of inflammatory bowel disease. Biochem Pharmacol. 2010; 79(2):229–238. DOI: 10.1016/j.bcp.2009.08.014
Wong C, Nguyen L, Noh S, Bray T, Bruno R, Ho E. Induction of regulatory T cells by green tea polyphenol EGCG. Immunol Lett. 2011;139(1–2):7–13. DOI: 10.1016/j.imlet.2011.04.009
Pae M, Ren Z, Meydani M, Shang F, Smith D, Meydani S, Wu D. Dietary supplementation with high dose of epigallocatechin-3-gallate promotes inflammatory response in mice. J Nutr Biochem. 2012;23(6):526–531. DOI: 10.1016/j.jnutbio.2011.02.006
Wu D, Wang J, Pae M, Meydani S. Green tea EGCG, T cells, and T cell-mediated autoimmune diseases. Mol Aspects Med. 2012;33(1):107–118. DOI: 10.1016/j.mam.2011.10.001
Zhang R1, Li Y, Wang W. Enhancement of immune function in mice fed high doses of soy daidzein. Nutr Cancer. 1997;29(1):24–28.
Marshall ME, Rhoades JL, Mattingly C, Jennings CD. Coumarin (1,2-benzopyrone) enhances DR and DQ antigen expressions by peripheral blood mononuclear cells in vitro. Mol Biother. 1991;3(4):204–206.
Del Carmen Juárez-Vázquez M, Josabad Alonso-Castro A, García-Carrancá A. Kaempferitrin induces immunostimulatory effects in vitro. J Ethnopharmacol. 2013; 148(1):337–340. DOI: 10.1016/j.jep.2013.03.072
Jakhar R, Paul S, Chauhan A, Kang S. Morin hydrate augments phagocytosis mechanism and inhibits LPS induced autophagic signaling in murine macrophage. Int Immunopharmacol. 2014;22(2):356–365. DOI: 10.1016/j.intimp.2014.07.020
Liu X, Zhao M, Wua K, Chai X, Yu H, Tao Z, Wang J. Immunomodulatory and anticancer activities of phenolics from emblica fruit ( Phyllanthus emblicaL.) Food Chem, 2012; 131:685–690.
Mossalayi M, Rambert J, Renouf E, Micouleau M, Mérillon J. Grape polyphenols and propolis mixture inhibits inflammatory mediator release from human leukocytes and reduces clinical scores in experimental arthritis. Phytomedicine. 2014;21(3):290–297. DOI: 10.1016/j.phymed.2013.08.015
Daniel P, Falcioni F, Berg AU, Berg P. Influence of cianidanol on specific and non-specific immune mechanisms. Methods Find Exp Clin Pharmacol. 1986;8(3):139–145.
Melgarejo E, Medina MA, Sánchez-Jiménez F, Urdiales JL. Epigallocatechin gallate reduces human monocyte mobility and adhesion in vitro. Br J Pharmacol. 2009;158(7):1705–1712. DOI: 10.1111/j.1476-5381.2009.00452.x
Gelderblom M, Leypoldt F, Lewerenz J, Birkenmayer G, Orozco D, Ludewig P, Thundyil J, Arumugam T, Gerloff C, Tolosa E, Maher P, Magnus T. The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice. J Cereb Blood Flow Metab. 2012;32(5):835–843. DOI: 10.1038/jcbfm.2011.189
Hämäläinen M, Nieminen R, Vuorela P, Heinonen M, Moilanen E. Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-κB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-κB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediators Inflamm 2007;2007:45673. doi:10.1155/2007/45673
Cho YC, Kim HJ, Kim YJ, Lee KY, Choi HJ, Lee IS, Kang BY. Differential anti-inflammatory pathway by xanthohumol in IFN-gamma and LPS-activated macrophages. Int Immunopharmacol. 2008;8(4):567–573. DOI: 10.1016/j.intimp.2007.12.017
Zanotti Simoes Dourado G, de Abreu Ribeiro L, Zeppone C, Borges C. Orange juice and hesperidin promote differential innate immune response in macrophages ex vivo. Int J Vitam Nutr Res. 2013;83(3):162–167. DOI: 10.1024/0300-9831/a000157
Saroni Arwa P, Zeraik ML, Ximenes VF, da Fonseca LM, Bolzani Vda S, Siqueira Silva DH. Redox-active biflavonoids from Garcinia brasiliensisas inhibitors of neutrophil oxidative burst and human erythrocyte membrane damage. J Ethnopharmacol 2015; 174:410–418. DOI: 10.1016/j.jep.2015.08.041
Chang MC, Chang HH, Wang TM, Chan CP, Lin BR, Yeung SY, Yeh CY, Cheng RH, Jeng JH. Antiplatelet effect of catechol is related to inhibition of cyclooxygenase, reactive oxygen species, ERK/p38 signaling and thromboxane A2 production. PLoS One. 2014; 9(8):e104310. DOI: 10.1371/journal.pone.0104310. ECollection 2014
Wang JP, Tsao LT, Raung SL, Lin CN. Investigation of the inhibitory effect of broussochalcone A on respiratory burst in neutrophils. Eur J Pharmacol. 1997;320(2–3):201–208.
Hwang TL, Leu YL, Kao SH, Tang MC, Chang HL. Viscolin, a new chalcone from Viscum coloratum, inhibits human neutrophil superoxide anion and elastase release via a cAMP-dependent pathway. Free Radic Biol Med. 2006;41(9):1433–1441.
Pagonis C, Tauber AI, Pavlotsky N, Simons E. Flavonoid impairment of neutrophil response. Biochem Pharmacol. 1986;35(2):237–245.
Khan A, Ali A, Santercole V, Paglietti B, Rubino S, Urooj S, Farooqui K, Farooqui A. Camellia sinensismediated enhancement of humoral immunity to particulate and non-particulate antigens. Phytother Res 2016;30:41–48.
Allam G, Abuelsaad A, Alblihed M, Alsulaimani A. Ellagic acid reduces murine schistosomiasis mansoni immunopathology via up-regulation of IL-10 and down-modulation of pro-inflammatory cytokines production. Immunopharmacol Immunotoxicol. 2016;38(4):286–297. DOI: 10.1080/08923973.2016.1189561
Oliveira R, Narciso C, Bisinotto R, Perdomo M, Ballou M, Dreher M, Santos J. Effects of feeding polyphenols from pomegranate extract on health, growth, nutrient digestion, and immunocompetence of calves. J Dairy Sci. 2010;93(9):4280–4291. DOI: 10.3168/jds.2010-3314
Brattig N, Diao G, Berg P. Immunoenhancing effect of flavonoid compounds on lymphocyte proliferation and immunoglobulin synthesis. Int J Immunopharmacol. 1984;6(3):205–215.
Lyu SY, Park WB. Production of cytokine and NO by RAW 264.7 macrophages and PBMC in vitroincubation with flavonoids. Arch Pharm Res. 2005;28(5):573–581. DOI:10.1007/BF02977761
Xiao J, Zhai H, Yao Y, Wang C, Jiang W, Zhang C, Simard A, Zhang R, Hao J. Chrysin attenuates experimental autoimmune neuritis by suppressing immuno-inflammatory responses. Neuroscience 2014;262:156–164. DOI: 10.1016/j.neuroscience.2014.01.004
Cox GW, Orosz CG, Fertel RH. 8-Methoxypsoralen inhibits lymphocyte proliferation in vitroin the absence of ultraviolet radiation. Int J Immunopharmacol. 1987;9(4):475–481.
Cox GW, Orosz CG, Lewis MG, Olsen RG, Fertel RH. Evidence that 8-methoxypsoralen (8-MOP) is a T-lymphocyte immunomodulatory agent. Int J Immunopharmacol. 1988; 10(6):773–781. DOI:10.1016/0192-0561(88)90031-8
Cho Y, You S, Kim H, Cho C, Lee I, Kang B. Xanthohumol inhibits IL-12 production and reduces chronic allergic contact dermatitis. Int Immunopharmacol. 2010;10(5):556–561. DOI: 10.1016/j.intimp.2010.02.002
Cho YC, Lee SH, Yoon G, Kim HS, Na JY, Choi HJ, Cho CW, Cheon SH, Kang BY. Licochalcone E reduces chronic allergic contact dermatitis and inhibits IL-12p40 production through down-regulation of NF-kappa B. Int Immunopharmacol. 2010;10(9):1119–1126. DOI: 10.1016/j.intimp.2010.06.015
Zhang X, Wang G, Gurley E, Zhou H. Flavonoid apigenin inhibits lipopolysaccharide-induced inflammatory response through multiple mechanisms in macrophages. PLoS One. 2014;9(9):e107072. DOI: 10.1371/journal.pone.0107072
Kwon D, Ju S, Youn G, Choi S. Park J. Suppression of iNOS and COX-2 expression by flavokawain A via blockade of NF-κB and AP-1 activation in RAW 264.7 macrophages. Food Chem Toxicol. 2013;58:479–486. DOI: 10.1016/j.fct.2013.05.031
Murali V, Kuttan G. Curculigoside augments cell-mediated immune responses in metastatic tumor-bearing animals. Immunopharmacol Immunotoxicol. 2016;38(4):264–269. DOI: 10.1080/08923973.2016.1188401
Han J, Jin Y, Kim H, Park K, Lee W, Jeong T. Lavandulyl flavonoids from Sophora flavescenssuppress lipopolysaccharide-induced activation of nuclear factor-kappaB and mitogen-activated protein kinases in RAW264.7 cells. Biol Pharm Bull. 2010;33(6):1019–1023. http://doi.org/10.1248/bpb.33.1019
Kawamoto Y, Ueno Y, Nakahashi E, Obayashi M, Sugihara K, Qiao S, Iida M, Kumasaka M, Yajima I, Goto Y, Ohgami N, Kato M, Takeda K. Prevention of allergic rhinitis by ginger and the molecular basis of immunosuppression by 6-gingerol through T cell inactivation. J Nutr Biochem 2016;27:112–122.
Liu Z, Zhong J, Gao E, Yang H. Effects of glycyrrhizin acid and licorice flavonoids on LPS-induced cytokines expression in macrophage. Zhongguo Zhong Yao Za Zhi. 2014; 39(19):3841–3845.
Yasui M, Matsushima M, Omura A, Mori K, Ogasawara N, Kodera Y, Shiga M, Ito K, Kojima S, Kawabe T. The suppressive effect of quercetin on toll-like receptor 7-mediated activation in alveolar macrophages. Pharmacology. 2015;96(5–6):201–209. DOI: 10.1159/000438993
Itoh A, Isoda K, Kondoh M, Kawase M, Kobayashi M, Tamesada M, Yagi K. Hepatoprotective effect of syringic acid and vanillic acid on concanavalin a-induced liver injury. Biol Pharm Bull. 2009;32(7):1215–1219. http://doi.org/10.1248/bpb.32.1215
Kolbe L, Immeyer J, Batzer J, Wensorra U, tom Dieck K, Mundt C, Wolber R, Stäb F, Schönrock U, Ceilley RI, Wenck H. Anti-inflammatory efficacy of Licochalcone A: correlation of clinical potency and in vitroeffects. Arch Dermatol Res. 2006:298(1):23–30.
Park M, Park J, Cho M, Oh H, Heo Y, Woo Y, Heo Y, Park M, Park H, Park S, Kim H, Min J. Grape seed proanthocyanidin extract (GSPE) differentially regulates Foxp3(+) regulatory and IL-17(+) pathogenic T cell in autoimmune arthritis. Immunol Lett. 2011; 135(1–2):50–58. DOI: 10.1016/j.imlet.2010.09.011
Kumazawa Y, Kawaguchi K, Takimoto H. Effects of flavonoids on acute and chronic inflammatory responses caused by tumor necrosis factor a. Curr Pharm Des 2006;12: 4271–4279.
Hatziieremia S, Gray AI, Ferro VA, Paul A, Plevin R. The effects of cardamonin on lipopolysaccharide-induced inflammatory protein production and MAP kinase and NFkappaB signalling pathways in monocytes/macrophages. Br J Pharmacol. 2006;149(2):188–198.
Jung W, Choi I, Lee D, Yea S, Choi Y, Kim M, Park S, Seo S, Lee S, Lee C, Park Y, Choi I. Caffeic acid phenethyl ester protects mice from lethal endotoxin shock and inhibits lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in RAW 264.7 macrophages via the p38/ERK and NF-kappaB pathways. Int J Biochem Cell Biol. 2008;40(11):2572–2582. DOI: 10.1016/j.biocel.2008.05.005
Kim M, Kim S. Inhibitory effect of astragalin on expression of lipopolysaccharide-induced inflammatory mediators through NF-κB in macrophages. Arch Pharm Res. 2011; 34(12):2101–2107. DOI: 10.1007/s12272-011-1213-x
Manna K, Das U, Das D, Kesh S, Khan A, Chakraborty A, Dey S. Naringin inhibits gamma radiation-induced oxidative DNA damage and inflammation, by modulating p53 and NF-κB signaling pathways in murine splenocytes. Free Radic Res. 2015;49(4):422–439. DOI: 10.3109/10715762.2015.1016018
Rim H, Cho W, Sung S, Lee K. Nodakenin suppresses lipopolysaccharide-induced inflammatory responses in macrophage cells by inhibiting tumor necrosis factor receptor-associated factor 6 and nuclear factor-κB pathways and protects mice from lethal endotoxin shock. J Pharmacol Exp Ther. 2012;342(3):654–664. DOI: 10.1124/jpet.112.194613
Qureshi A, Tan X, Reis J, Badr M, Papasian C, Morrison D, Qureshi N. Inhibition of nitric oxide in LPS-stimulated macrophages of young and senescent mice by δ-tocotrienol and quercetin. Lipids Health Dis 2011;10:239. DOI: 10.1186/1476-511X-10-239
Bremner P, Heinrich M. Natural products and their role as inhibitors of the pro-inflammatory transcription factor NF-kB, Phytochem Rev 2005;4:27–37.