Open access

Immunoregulatory Properties of Acute Phase Proteins — Specific Focus on α1-Antitrypsin

Written By

S. Janciauskiene, S. Wrenger and T. Welte

Submitted: September 18th, 2012 Published: July 24th, 2013

DOI: 10.5772/56393

Chapter metrics overview

2,763 Chapter Downloads

View Full Metrics

1. Introduction

Activation of innate immune cells in response to various insults is a part of the host defence. However, if uncontrolled, this inflammatory response induces persistent hyper-expression of pro-inflammatory mediators and tissue damage. Tight control of pro-inflammatory pathways is therefore critical for immune homeostasis and host survival.

A complex network of activating and regulatory pathways controls innate immune responses; the hepatic acute-phase response is one of the crucial contributors to this regulation. For example, in response to infection or tissue injury within few hours the pattern of protein synthesis by the liver is drastically altered, i.e. increased expression of the so called positive acute phase proteins (APPs) like C-reactive protein (CRP), alpha1-antitrypsin (AAT) or alpha1-acid glycoprotein (AGP) and decreased expression of transthyretin, retinol binding protein, cortisol binding globulin, transferrin and albumin, which represent the group of negative APPs. This production of APPs in hepatocytes is controlled by a variety of cytokines released during inflammation whereas leading regulators are IL-1- and IL-6-type cytokines having additive, inhibitory, or synergistic effects. For instance, IL-1β is shown to almost completely abrogate IL-6-induced production of α2-macroglobulin and α1-antichymotrypsin but, in contrast, to enhance production of CRP and serum amyloid A. No doubt, this specific regulation of AAPs expression plays a critical role in the regulation of the host innate immune responses.


2. Alpha1-antitrypsin and the acute phase response

AAT, also referred to as alpha1-proteinase inhibitor or SERPINA1, is the most abundant serine protease inhibitor in human blood. AAT consists of a single polypeptide chain of 394 amino acid residues containing one free cysteine residue and three asparagines-linked carbohydrate side-chains. AAT is mainly produced by liver cells but can also be synthesized by blood monocytes, macrophages, pulmonary alveolar cells, and by intestinal and corneal epithelium (Geboes et al., 1982; Perlmutter et al., 1985; Ray et al., 1982). In terms of tissue expression AAT has been demonstrated in the kidney, stomach, small intestine, pancreas, spleen, thymus, adrenal glands, ovaries and testes. De novo synthesis of AAT has also been demonstrated in human cancer cell lines. These observations indicate that AAT transcription is relatively widespread. In fact, tissue-specific promoter activity for AAT has been reported in the liver, the major source of AAT, and alternative promotors for other tissues that express the protein (Kalsheker et al., 2002; Tuder et al., 2010). Interestingly, AAT expression also shows some degree of substrate and/or auto-regulation: upon exposure to neutrophil and pancreatic elastases, either alone or as a complex of AAT, enhanced synthesis of AAT was observed (Perlmutter et al., 1988).

The normal daily rate of synthesis of AAT is approximately 34 mg/kg body weight and the protein is cleared with a half-life of 3 to 5 days. This results in high plasma concentrations ranging from 0.9 to 2 mg/ml when measured by nephelometry. In addition to high circulating levels in blood, AAT is also present in saliva, tears, milk, semen, urine and bile (Berman et al., 1973; Chowanadisai & Lonnerdal, 2002; Huang, 2004; Janciauskiene et al., 1996; Poortmans & Jeanloz, 1968). The distribution of the protein in the tissues is not uniform. For example, in the epithelial lining fluid of the lower respiratory tract its concentration is approximately 10% of plasma levels (Janciauskiene, 2001).

As an acute-phase reactant, circulating AAT levels increase rapidly (3 to 4 fold) in response to inflammation or infection. The concentration of AAT in plasma also increases during oral contraceptive therapy and pregnancy. During an inflammatory response, tissue concentrations of AAT may increase as much as 11-fold as a result of local synthesis by resident or invading inflammatory cells (Boskovic & Twining, 1997). Blood monocytes and alveolar macrophages can contribute to tissue AAT levels in response to inflammatory cytokines (IL-6, IL-1 and TNFα) and endotoxins (Knoell et al., 1998; Perlmutter & Punsal, 1988). Recent data demonstrate that AAT expression by alpha and delta cells of human islets (Bosco et al., 2005) and intestinal epithelial cells (Faust et al., 2001) is also enhanced by pro-inflammatory cytokines. AAT synthesis by corneal epithelium, on the other hand, appears to be under the influence of retinol, IL-2, fibroblast growth factor-2, and insulin-like growth factor-I (Boskovic & Twining, 1997; Boskovic & Twining, 1998). Oncostatin M, a member of the IL-6 family was shown to induce AAT production by human bronchial epithelial cells. This effect of oncostatin M was in turn modulated by TGF-β and IFN-γ at both the protein and mRNA level. IFN-γ decreased oncostatin M-induced AAT production whilst TGF-β induced a significant and synergistic up-regulation of AAT that was not observed in a hepatocyte cell line (Boutten et al., 1998). Study by Shin and coworkers (Shin et al., 2011) have demonstrated that nasal lavage fluids from the patients with allergic rhinitis contains AAT and that the levels of nasal AAT markedly increase in response to allergenic stimulation. This response seems to be closely associated with the activation of eosinophils induced by allergen-specific IgA. In allergen-induced nasal inflammation, AAT might be a byproduct of the activated inflammatory cells, and is thus implicated in the allergic immune response (Shin et al., 2011).

According to recent studies, activated neutrophils and eosinophils can store and secrete AAT, which plays a role in protection of tissues at local inflammation sites (Johansson et al., 2001; Paakko et al., 1996). Furthermore, Clemmensen and coworkers found that the mRNA for AAT increases during maturity of the myeloid cell precursors and is even higher in blood neutrophils. This in itself is quite remarkable as blood neutrophils are generally considered transcriptionally inactive, but it is even more striking that the transcriptional activity of the AAT gene increases further when neutrophils migrate into tissues (Clemmensen et al., 2011). Moreover, circulating AAT produced by liver cells can enter granulocytes and is stored in the secretory vesicles (Borregaard et al., 1992).


3. Protective anti-inflammatory, immunomodulatory and antimicrobial effects of alpha1-antitrypsin

Findings from different experimental models provide clear evidence that AAT expresses broad anti-inflammatory and immunoregulatory activities (Figure 1). AAT has been reported to inhibit neutrophil superoxide production, adhesion, and chemotaxis, to enhance insulin-induced mitogenesis in cell lines and to induce IL-1 receptor antagonist, a negative regulator to IL-1 signalling, in blood monocytes and neutrophils (Tuder et al., 2010). Findings that AAT enhances the synthesis of transferrin receptor and ferritin revealed a role of AAT in iron metabolism (Graziadei et al., 1997). In murine models, exogenous human AAT protects islet cell allografts from rejection and increase survival in an allogeneic marrow transplantation models. In other models AAT therapy protects against TNF-α / endotoxin induced lethality, cigarette smoke induced emphysema and inflammation and even suppressed bacterial proliferation during infections ((Lewis, 2012), review). Furthermore, human AAT given to mice during renal ischemia–reperfusion (I/R) injury lessens tissue injury and attenuated organ dysfunction (Daemen et al., 2000).

Figure 1.

Selected anti-inflammatory and immunoregulatory activities of AAT.

These beneficial impacts of AAT are incompletely understood, although exscinding knowledge suggests that AAT promotes a switch from pro-inflammatory to anti-inflammatory pathways necessary for the resolution of inflammation.

AAT has long been thought of as a main inhibitor of neutrophil elastase, proteinase 3, and other serine proteases released from activated human neutrophils during an inflammatory response. In fact, the rate of formation of the AAT/neutrophil elastase inhibitory complex is one of the fastest known for serpins (6.5x 107 M-1 s-1) (Gettins, 2002). The structure of AAT consists of three β-sheets (A, B, C) and 9 α-helices (A-I). The inhibitory active conformation of AAT like for other serine protease inhibitors represents a metastable state, characterized by an exposed reactive center loop that acts as bait for the target enzyme (Stocks et al., 2012). Cleavage of the scissile bond in the loop results in a large conformational change in which the reactive site loop migrates and is inserted into the pre-existing β-sheet A forming a very stable complex between the inhibitor and the protease. This reaction results in a rapid and irreversible inactivation of both AAT and its target protease.

As an inhibitor, AAT also shows true substrate-like behaviour and cleavage without complex formation. Novel studies show that AAT, without forming complexes, inhibits the activity of gelatinase B (MMP9) and caspases-1 and -3 that play an essential role in cell apoptosis. AAT also inactivates the catalytic domain of matriptase, a cell surface serine protease involved in the activation of epithelial sodium channels. In addition, recent evidence has emerged on the ability of AAT to inhibit the matrix metalloprotease, ADAM-17 (Bergin et al., 2010) and aspartic-cysteine protease, calpain I (Al-Omari et al., 2011). Calpain I activity has been implicated in neutrophil apoptosis (Chen et al., 2006), chemotaxis (Lokuta et al., 2003) and adhesion (Wiemer et al., 2010). In fact, AAT inhibits neutrophil adhesion, chemotaxis (Al-Omari et al., 2011; Bergin et al., 2010) and apoptosis (Zhang et al., 2007). The mechanism behind these latter effects of AAT might be directly linked to its ability to inhibit calpain I activity.

So far, it is assumed that anti-inflammatory and immunomodulatory functions of AAT are dependent on its metastable native conformation (with inhibitory activity); however, this has not been proven. Earlier studies by Churg and collaborators have demonstrated that oxidized AAT (without elastase inhibitory activity) is effective in preventing neutrophil influx and lung tissue damage in a silica-induced inflammation model in mice (Churg et al., 2001). We also reported that oxidized AAT (again without elastase inhibitory activity) reduces endotoxin-induced TNF-α, IL-8, MCP-1, and IL-1 release in human monocytes in vitro (Janciauskiene et al., 2004). We also found that the pattern of gene expression regulated in human primary lung endothelial cells by native and oxidized AAT was similar with neither inducing pro-inflammatory gene expression (Subramaniyam et al., 2008).

Moreover, a specific short carboxyl terminal peptide of AAT which doesn´t inhibit elastase is a more potent inhibitor of LPS-induced TNF-α and IL-8 production than native AAT (Amelinckx et al., 2011; Subramaniyam et al., 2006)

Recently, we examined the effects of plasma purified AAT in LPS-induced acute lung injury in wild-type (WT) and neutrophil elastase-deficient mice as well as in neutrophils isolated from the bone marrow of WT and elastase-deficient mice. Analyses of lung lavage fluids and tissues revealed that, regardless from the mouse strain, AAT induced a 50% decrease in LPS-induced neutrophil counts as well as a reduction in the lavage fluid levels of IL-8 and TNF-α. Furthermore, AAT inhibited the ability of LPS to increase TNF-α, DNA damage-inducible transcript 3 and X-box binding protein 1 gene expression in the lung parenchyma (Jonigk et al., PNAS, in press).

These findings provide clear evidence that inhibition of elastase is not the sole mechanism behind the anti-inflammatory and immunoregulatory activities of AAT. The responsible molecular mechanisms remain to be elucidated.


4. Interaction with other macromolecules and cell surface ‘receptors’ and signalling mechanisms

AAT shows the property to interact with other proteins. For example, in sera from patients with myeloma and Bence-Jones proteinemia complexes between AAT and the kappa light chain of immunoglobulins were detected (Laurell & Thulin, 1975). In plasma from diabetic subjects, complexes between AAT and factor Xia, AAT and heat shock protein-70 as well as AAT and glucose were detected (Murakami et al., 1993; Finotti & Pagetta, 2004; Hall et al., 1986). Moreover, complexes between AAT and immunoglobulin A have been detected in the sera and synovial fluid of patients with rheumatoid arthritis, systemic lupus erythematosus and ankylosing spondylitis (Adam & Bieth, 1996). Localization of AAT-low-density-lipoprotein (LDL) complexes in atherosclerotic lesions and enhanced degradation of AAT-LDL by macrophages suggested the involvement of the complex in atherogenesis (Mashiba et al., 2001).

Earlier studies have shown that cellular internalization and degradation of AAT-elastase-, or AAT-trypsin-complexes, but not of the native form of AAT, is mediated by serpin-enzyme complex (SEC) receptor (Perlmutter et al., 1990), low-density lipoprotein receptor related protein (Poller et al., 1995) and very-low-density lipoprotein receptor which require intact raft lipid environment (Wu & Gonias, 2005; Yoon et al., 2007).

Recent studies provide new evidence that clathrin-mediated endocytosis (Sohrab et al., 2009) and the caveolar pathway (Aldonyte et al., 2008) and Fc receptor(s) (Bergin et al., 2010) might be responsible for the interaction and entry of native AAT into the cell. Experimental studies have shown that various APPs, like C-reactive protein (CRP), interact with lipid rafts (Ji et al., 2009) and therefore, gave support for the hypothesis that APPs-lipid raft interaction may be a putative mechanism responsible for the diverse activities of APPs during inflammation.

Lipid rafts are dynamic assemblies of proteins and lipids that play a central role in various cellular processes, including membrane sorting and trafficking, cell polarization, and signal transduction (Baird et al., 1999; Janes et al., 2000; Zhu et al., 2006). Biochemical and cell-biological studies have identified cholesterol as a key factor determining raft and related structure (e.g., caveolae) stability and organization in mammalian cell membranes, and have shown that the equilibrium between free and raft cholesterol plays a critical role in lipid raft function and cell signalling (Golub et al., 2004; Gombos et al., 2006). Many proteins involved in signal transduction, such as Src family kinases, G proteins, growth factor receptors, mitogen-activated protein kinase and protein kinase C are predominantly found in lipid rafts, which act as signaling platforms by bringing together (i.e., colocalizing) various signaling components (Simons & Toomre, 2000).

Our studies on the putative role of lipid rafts and lipid raft cholesterol for AAT entry into monocytes revealed that exogenously added AAT becomes translocated into lipid rafts in the same fraction as the lipid raft marker flotillin (Slaughter et al., 2003; Subramaniyam et al., 2010). It is well documented that plasma membranes of mammalian cells contain a 30–50% molar fraction of cholesterol (Warnock et al., 1993), which is the dynamic glue for the lipid raft assembly (Simons & Toomre, 2000). Taken with the finding that exogenous AAT localizes in the lipid raft prompted us to examine whether altering the integrity of the lipid raft cholesterol would affect AAT-monocyte association. In fact, AAT association with monocytes was remarkably inhibited by various cholesterol depleting/efflux-stimulating agents such as nystatin, filipin, methyl-betacyclodextrin, oxidized low-density lipoprotein and high density lipoproteins, and conversely, enhanced by free cholesterol. We had previously identified that AAT can directly interact with free cholesterol in vitro (Janciauskiene & Eriksson, 1993). In support, we confirmed that AAT /monocyte association per se depletes lipid raft cholesterol as characterized by the activation of extracellular signal-regulated kinase 2, increased HMG-CoA reductase expression, formation of cytosolic lipid droplets, and a complete inhibition of oxidized low-density lipoprotein and oxidized phopspholipid uptake by monocytes (Subramaniyam et al., 2010).

Lipid rafts act as platforms, bringing together molecules essential for the activation of immune cells, but also separating such molecules when the conditions for activation are not appropriate (Ehrenstein et al., 2005). We hypothesize that AAT/ lipid raft interaction and cholesterol depletion contributes to re-organize membrane domains and facilitate the formation of compartment-specific signalling platforms. As a consequence, several events can occur intracellularly like transient release of calcium and Na+/K+-ATPase-EGFR-Src-caveolin-1 complex formation leading to an increased tyrosine phosphorylation of caveolin-1 and the activation of the Rac1-Cdc42-ERK cascade, and transient activation of hemoxygenase-1. It has been previously reported that exogenous AAT is rapidly internalized into the cells and is localized in the plasma membranes and in the cytoplasm (Sohrab et al., 2009). Whether internalized AAT is further trafficking to the interstitium or remains within the cells is unknown. As a matter of fact, AAT is shown to interact with the transferrin receptor (Graziadei et al., 1994) which is constantly internalized via endocytic vesicles that fuse with early endosomes and returns to the plasma membrane through recycling endosomes (Harding et al., 1983). Thus it cannot be excluded that excess of internalized AAT trafficking occurs via transferrin receptor pathway.

Nevertheless, incorporation of AAT into membranes and transient depletion of cholesterol can affect recruitment of TLRs into lipid rafts subsequently desensitizing signalling by bacterial endotoxins and resulting in consequent reduction of the pro-inflammatory response. In support, human innate immune cells stimulated with bacterial lipopolysaccharide (LPS) in the presence of AAT show suppressed TNFα, IL-8, IL-12 and IL-1β, but enhanced IL-10 production (Figure 2) (Janciauskiene et al., 2004; Nita et al., 2005).

Figure 2.

Hypothesis of the immune modulator effect of AAT. A: LPS signalling and cell activation; B: effects of AAT on LPS signalling and cell activation.

In general, this hypothesis provides the basis for future studies linking bioactivities of acute phase proteins to signalling pathways associated with lipid rafts. Lipid rafts are therapeutic targets for various diseases and studies on physiological significance of interaction between acute phase proteins and lipid rafts of great importance.


5. Diseases associated with AAT deficiency

The clinical relevance of AAT is highlighted in individuals with inherited deficiency in circulating AAT who have an increased susceptibility to early onset pulmonary emphysema, and liver as well as pancreatic diseases. The most interesting AAT variants associated with deficiency are the S and Z genes commonly found in Europeans. Both S and Z AAT result from single amino acid substitutions. In the S variant there is a substitution of a valine residue for glutamate at position 264 (Val264Glu) (Curiel et al., 1989). The Z mutation (Glu342Lys) results from the substitution of a positively charged lysine for a negatively charged glutamine at the base of the reactive centre. Severe ZZ deficiency of AAT is characterized by a decrease in serum AAT levels below a protective threshold of 11 mmol/L (Fregonese et al., 2008; Hubbard & Crystal, 1988) and is associated with increased but variable risk for the development of lung emphysema (Janciauskiene et al., 2010).

From retrospective studies we also know that up to 25% of those with severe AAT deficiency will suffer from liver cirrhosis and for liver cancer in late adulthood (Propst et al., 1994). Also heterozygous AAT deficiency is a cofactor in the development of chronic liver diseases (Kok et al., 2007). Adults with AAT deficiency–associated genotypes develop liver disease less frequently than pulmonary manifestations. However, AAT is a relevant cause for liver cirrhosis, after viral hepatitis, alcohol abuse, and chronic cholangitis. Other factors that can also predispose AAT-deficient individuals to liver disease are male sex and obesity (Bowlus et al., 2005).The underlying cause may be the intrahepatic accumulation of polymerized AAT molecules. The polymers of Z-mutant AAT can be identified in endoplasmic reticulum by the electron microscopy as diastase resistant inclusion bodies reacting positively with PAS-staining (Periodic acid-Schiff). Intracellular inclusion bodies in the liver have also been observed with other polymer-forming phenotypes of AAT deficiency (Mmalton (52Phe del), and Siiyama (Ser53Phe) (Tuder et al., 2010).

Figure 3.

Schematic diagram depicting the role of polymers of α1-Antitrypsin (AAT) in the development of liver and lung diseases. A) AAT polymers stained with rabbit polyclonal antibody against human AAT, B) AAT polymers stained with mouse monoclonal ATZ11 antibody against human Z polymers.

Inherited AAT deficiency is occasionally associated with antiproteinase-3-associated vasculitis (Wegener’s granulomatosis), necrotizing panniculitis and aneurysms of the abdominal aorta and brain arteries. AATD has also been associated with a number of other inflammatory diseases, although the association is only moderate or weak. These include bronchial asthma, bronchiectasis, rheumatoid arthritis, psoriasis, chronic urticaria, glomerulonephritis, pancreatitis and pancreatic tumors, multiple sclerosis, fibromyalgia and other conditions reported occasionally (Janciauskiene et al., 2011)

Remarkably, associations have been found between reduced plasma AAT levels and HIV-1 infection, hepatitis, diabetes mellitus, systemic vasculitis and necrotizing panniculitis (Lewis, 2012; Tuder et al., 2010).

5.1. AAT augmentation therapy

Given the concept of the protease/antiprotease imbalance role in causing emphysema, augmentation of circulating AAT was introduced 30 years ago to treat emphysema patients with severe ZZ deficiency of AAT. Augmentation therapy with human AAT has been performed for over a decade in the United States and in a number of European countries. Worldwide, more than 4,000 patients are currently receiving regular AAT substitution. Most patients receive weekly intravenous application of 3–5 g AAT (60 mg/kg body weight), which is derived from pooled human plasma. Patients with emphysema may be considered for augmentation if their serum concentration is below 0.8 g/L (≤ 11 µmol/L), if their post-bronchodilator FEV1 is between 35% and 60% of predicted, or if their annual decline of FEV1 is more than 100 mL (for review see (Mohanka et al., 2012))

Substitution therapy has been studied in a few clinical trials, and the evidence for its efficacy is limited. A last double-blind, placebo-controlled trial EXACTLE (the EXAcerbations and computed tomography (CT) scan as Lung Endpoints), was designed to explore the use of CT densitometry as an outcome measure for the assessment of the effect of AAT augmentation therapy on the progression of emphysema in individuals with inherited AAT deficiency (Stockley et al., 2010). This study showed that the rate of lung density decline was reduced by the intravenous augmentation therapy, and although the exacerbation frequency was unaltered by this treatment, a reduction in severity of exacerbations was observed.

To date fewer than 50 cases of panniculitis associated with various phenotypes of AAT deficiency have been reported (Piliang & Stoller, 2008). The clinical features that distinguish the AAT deficiency-associated panniculitis include higher frequency of ulceration, a vigorous neutrophilic response and histological evidence of both necrosis and elastin breakdown (Smith et al., 1989). In support of AAT deficiency as a contributor to the inflammatory pathogenesis of panniculitis, a few case reports provide evidence that the infusion of purified pooled human AAT induces a rapid clinical resolution of panniculitis (Gross et al., 2009; O'Riordan et al., 1997; Furey et al., 1996).

The putative association between AAT deficiency and vasculitis (Wegener’s granulomatosis) is based on the fact that AAT deficiency variants occur more frequently among individuals with multisystem vascultitis (anti-neutrophilic cytoplasmic antibodies (C-ANCA) or anti-protease-3 (PR-3) and glomerulonephritis (Esnault et al., 1993; O'Donoghue et al., 1993; Montanelli et al., 2002). Moreover, since AAT plays an important role in inhibiting PR3, it has been suggested that AAT deficiency could trigger an autoimmune response due to increased extracellular exposure to PR3 (Esnault et al., 1997). Alternatively, although unproven, it is conceivable that circulating Z AAT polymers could prompt a vascular response.

5.2. New perspectives for use of the AAT augmentation therapy

Administration of exogenous human plasma-derived AAT is used in various animal models to test the value of AAT augmentation. Several studies report that administration of AAT results in a change from the pro-inflammatory to the anti-inflammatory pathways that is necessary for the resolution of inflammation. Cystic Fibrosis (CF) is a condition caused by a known gene defect which predisposes individuals to chronic lung inflammation and infection. To date work has demonstrated that CF neutrophils secrete abnormally high levels of the pro-inflammatory cytokines, such as IL-8 and TNFα, and proteolytic enzymes specifically elastase which not only causes lung parenchymal damage, but can also perpetuate a vicious cycle of inflammation by inducing expression of the neutrophil chemoattractant, IL-8, from bronchial epithelial cells. Therefore, the interest in the application of treatment with inhaled AAT in CF lung disease is discussed (Siekmeier, 2010)

Based on preclinical and clinical studies, it is suggested that AAT therapy can be successfully used for non-deficient individuals with Type-1 and Type-2 diabetes, acute myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, cystic fibrosis, transplant rejection, graft-versus-host-disease and multiple sclerosis. AAT also appears to be antibacterial and an inhibitor of viral infections, such as influenza and HIV, and is currently evaluated in clinical trials for Type-1 diabetes, cystic fibrosis and graft-versus-host-disease (Blanco et al., 2011; Lewis, 2012). New experimental approaches show that AAT therapy might be an option for arthritis treatment in a combination with doxycycline (Grimstein et al., 2010)

Thus, AAT can be used as potential treatment for a broad spectrum of inflammatory and immune-mediated diseases. Future treatment developments include gene therapy (via injections of viral or non-viral vector systems carrying the SERPINA1-cDNA), strategies to inhibit intra-hepatic AAT polymerization by small chemicals and chaperons, and inhibition of neutrophil elastase by using small molecules. Inhaled application of AAT is currently under development by several companies.


6. Immunoregulatory properties of other APPs

The change in the concentrations of APPs is universally used to monitor the course of the disease, independently of its nature (Parra et al., 2006). However, specific APPs can also modify inflammatory responses. The spectrum of action of various APPs extends to regulation of leukocyte migration, adhesion and production of inflammatory mediators, control of ion channels and mucus secretion, and modulation of other host defence mechanisms (table 1).

Acute-phase protein Main biological function
Proteins whose plasma concentration increase
C-reactive protein (CRP) Binding of phosphocholine (opsonin); immunoregulation
Alpha1-Acid Glycoprotein (AGP) Carry lipophilic compounds; immunoregulation
Serum amyloid A (SAA) Recruitment of immune cells; activation enzymes that degrade extracellular matrix
Fibronectin Wound healing
Ferritin Iron binding
Angiotensinogen Renin substrate
Complement factors: C3, C4, C9, factor B, C1 inhibitor, C4b-binding protein, mannose-binding lectin Enhancing phagocytosis of antigens, attracting macrophages and neutrophils, lysis membranes of foreign cells, clumping of antigen-bearing agents, altering the molecular structure of viruses
Coagulation and fibrinolysis factors: fibrinogen, plasminogen, tissue plasminogen activator, urokinase, protein S, vitronectin, plasminogen-activator inhibitor 1 Coagulation, degradation of blood clots, trapping invading microbes, chemotaxis
Ceruloplasmin Contains copper, has histaminase-and ferroxidase-activity; scavenges Fe2+ and free radicals
Haptoglobin (Hp) Binds haemoglobin; binds to CD11b/CD18 integrines
Alpha1-acid glycoprotein (AGP) Influences T-cell function; binds steroids
Interleukin1-receptor antagonist modulates a variety of interleukin 1 related immune and inflammatory responses
Alpha1-Antitrypsin (AAT) Inhibits proteolytic enzymes, immune-modulatory activity
Alpha1-Antichymotrypsin (ACT) Inhibits proteolytic enzymes
Alpha2-macroglobulin Inhibits proteolytic enzymes
Proteins whose concentration decrease
Albumin Regulates the osmotic pressure of blood
Transferrin Carrier protein, immunoregulation
Transthyretin Binds to aromatic compounds, carrier of retinol
Alpha-fetoprotein Binds various cations, fatty acids and bilirubin
Alpha2-HS glycoprotein Carrier protein, forms soluble complexes with calcium and phosphate
Thyroxine-binding globulin Binds thyroid hormone

Table 1.

Diverse functional activities of APPs.


7. Haptoglobin

Haptoglobin (Hp) is constitutively present in the plasma (normal plasma levels 0.3 to 3.0 mg/ml) and functions mainly as a scavenger protein for hemoglobin (Hb) that is released from erythrocytes. Hp-Hb complexes are rapidly cleared from the circulation predominantly in the liver (Kupfer cells) expressing the Hp-Hb receptor CD163 (Graversen et al., 2002). Hp not only prevents loss of Hb/iron by renal excretion and protects from iron-driven oxidative tissue damage, but also acts as a bacteriostatic protein. Hence, Hp restricts access of bacteria to iron that is essential for bacterial growth.

Plasma levels of Hp rise rapidly up to 2 to 5 folds during inflammation, specifically under conditions when there is an extensive amount of necrotic tissue in the wound. Like for other APPs, Hp synthesis is induced by various cytokines but also by ciliary neurotrophic factor. While IL-6 is the most efficient Hp inducer, IFN-γ blocks IL-6-induced Hp synthesis and TNF-β attenuates glucocorticoid-dependent expression of Hp (Baumann et al., 1990; Marinkovic & Baumann, 1990; Raynes et al., 1991; Yoshioka et al., 2002; Yu et al., 1999).

Although the liver is the major site of Hp expression, inducible expression of Hp is also found in lung, skin, spleen and kidney. This suggests that tissue levels of Hp are most likely regulated differently and vary from those in the blood (Abdullah et al., 2009). Therefore, locally expressed Hp, for example in the lungs, might be an important component of a local protection system with antioxidant, bacteriostatic and anti-inflammatory effects (Abdullah et al., 2012).

Hp influences almost every immune cell type of the innate as well as the adaptive immune response. As an example, binding of Hp-Hb to CD163 receptor on the monocytes and tissue macrophages (Kristiansen et al., 2001), induces anti-inflammatory and protective genes such as heme oxygenase-1 (HO-1) (Schaer et al., 2006). HO-1 is involved in heme catabolism that ends up with carbon monoxide, bilirubin and ferritin - all are known to exert potent anti-inflammatory and cytoprotective effects (Otterbein et al., 2003).

It has also been demonstrated that Hp inhibits respiratory burst in fMLP, arachindonic acid or opsonised zymosan-stimulated neutrophils (Oh et al., 1990). Moreover, Hp exerts inhibitory effects on fMLP-driven chemotaxis, and shows intracellular bactericidal activity against E. coli. (Rossbacher et al., 1999). Evidence exists for an intracellular uptake of Hp by peripheral blood neutrophils and monocytes via endocytosis and for the subsequent exocytosis of Hp following exposure to Candida albicans or TNF- α (Berkova et al., 1999; Wagner et al., 1996). Hp reduces LPS-induced pro-inflammatory effects by the selective suppression of TNF-α, IL-10 and IL-12 production in vivo and in vivo. The importance of anti-inflammatory and immune modulatory effects of Hp is confirmed by enhanced sensitivity of Hp knockout mice to LPS shock compared to wild type mice (Arredouani et al., 2005).

In addition to its effects on innate immunity, Hp also dampens adaptive immune response. It is a powerful inhibitor of the proliferative response of lymphocytes to phytohemagglutinin and concanavalin A, and depending on the concentration used Hp significantly inhibits or enhances mitogenesis in B-cells in response to LPS (Baseler & Burrell, 1983). Using highly purified human T lymphocytes Arredouani et al. presented evidence for a specific binding of Hp to resting and anti-CD3 stimulated CD4+ and CD8+ T cells and for a direct anti-proliferative effect of Hp on T lymphocytes (Arredouani et al., 2003).

Further evidence for the high importance of Hp as anti-oxidative and immunoregulatory compound arises from the existence of different Hp subtypes and their influence on different pathologies. Hp gene has been studied as a candidate gene for rheumatoid arthritis, systemic lupus erythematosus, primary sclerosing cholangitis, inflammatory bowel disease and diabetes mellitus type 2 (Marquez et al., 2012).

In human two allels code for Hp1 and Hp2 proteins resulting in Hp1-1, Hp2-2 homozygous and Hp2-1 heterozygous genotypes. Clinical studies show that Hp2-2 individuals suffering from diabetes mellitus have a higher risk of vascular complications, especially diabetic nephropathy, compared to Hp2-1 and Hp1-1 individuals (Asleh & Levy, 2005). Epidemiological data also show that Hp2-2 genotype is a major determinant of susceptibility to diabetic cardiovascular disease (Levy et al., 2010).

Functional differences between Hp1-1 and Hp2-2 on molecular level can be in part explained by the finding that the Hp1-1-Hb complex is endocytosed more rapidly by the CD163 pathway than Hp2-2-Hb. This results in a more effective clearance of Hb and less oxidative stress in Hp1-1 individuals (Asleh et al., 2003). Moreover, Hp2-2 individuals show greater immunological reactivity including higher antibody titers after vaccination compared to Hp1-1 and Hp2-1 individuals (Nevo & Sutton, 1968). When compare to Hp2-2-Hb, Hp1-1-Hb is related to a much greater production of anti-inflammatory cytokines, therefore, Hp1-1Hp results in a more Th2 directed balance between Th1 (inflammatory) and Th2 (anti-inflammatory) T helper cells. Recent findings provide evidence that Hp1-1 individuals are better protected against oxidative stress and Hp1-1 seems to have higher immunomodulatory effects than Hp 2-2 (Guetta et al., 2007).


8. Alpha-1-acid glycoprotein

Alpha-1-acid glycoprotein (AGP) also known as orosomucoid (ORM) is a heavily glycosylated (45 %) protein (Schmid et al., 1977) APG belongs to the immunocalin family, a lipocalin subfamily. Whereas the lipocalins function as carriers for small hydrophobic compounds, the immunocalins were shown to modulate inflammatory and immune responses (Logdberg & Wester, 2000; Hochepied et al., 2003). Though, the main biologic function of AGP remains unclear. Indeed, APG was found to be a major carrier for neutral and basic drugs in the blood (Kremer et al., 1988). Evidence also exists supporting a role for AGP in the maintenance of normal capillary permeability and selectivity by binding to the capillary vessel wall putatively as part of the glycocalyx, a dynamic endothelial surface layer of glycosaminoglycans, proteoglycans and absorbed plasma proteins (Curry et al., 1989; Fournier et al., 2000; Pries et al., 2000). Moreover, AGP stabilizes the biological activity of plasminogen activator inhibitor-1 (Smolarczyk et al., 2005).

AGP is a positive acute phase protein that under normal conditions circulates in human plasma at a concentration of 0.6 -1.2 mg/ml and rises up to 2- to 7-fold during acute phase response (Colombo et al., 2006; Kremer et al., 1988). Besides the liver, a main source for the circulating AGP levels, production of AGP occurs in human microvascular endothelial cells, pneumocytes, alveolar macrophages, neutrophils, monocytes and B and T lymphocytes (Sirica et al., 1979; Sorensson et al., 1999; Crestani et al., 1998; Martinez Cordero et al., 2008; Fournier et al., 1999; Theilgaard-Monch et al., 2005; Rahman et al., 2008; Gahmberg & Andersson, 1978; Dirienzo et al., 1987). Hepatic AGP expression is induced by the IL-1β, IL-6 and TNF-α and inhibited by the growth hormone (Barraud et al., 1996; Mejdoubi et al., 1999).

The immunomodulatory activities of AGP are specifically directed against exaggerated inflammatory response to tissue damage. For example, AGP in a concentration-dependent manner regulates neutrophil chemotactic migration and superoxide generation (Costello et al., 1984; Hochepied et al., 2003; Laine et al., 1990). AGP also inhibits monocyte chemotaxis and diminishes cellular leakage caused by histamine and bradykinin. Moreover, AGP induces secretion of soluble TNFα receptor and IL-1 receptor antagonist from peripheral blood monocytes. (Tilg et al., 1993; Samak et al., 1982; Muchitsch et al., 1996).

The effects of AGP on lymphocytes are mainly immunosuppressive. AGP significantly suppresses induced synthesis of IL-2 and proliferation of lymphocytes (Chiu et al., 1977; Elg et al., 1997). Notably, different glycan variants of AGP show different degrees of inhibition of lymphocyte proliferation (Bennett & Schmid, 1980). The Con A non-reactive fraction of AGP (AGP-A) inhibits anti-CD3 stimulated lymphocyte proliferation stronger than Con A reactive AGP forms emphasizing the importance of the carbohydrate moiety of AGP (Pos et al., 1990).

In vivo AGP has been found to protect mice against TNF-α induced lethal shock but not from LPS-induced lethality or Fas-mediated cell death in lethal hepatitis. These findings imply that the protecting effects of AGP are, most likely, TNF-α -specific (Muchitsch et al., 1998; Van Molle et al., 1999).

Pro-inflammatory and immuno-stimulatory effects of AGP have been described, too. Previous studies demonstrated that AGP activates monocytes to produce IL-1β, IL-6, IL-12, TNF-α and tissue factor (Su & Yeh, 1996; Tilg et al., 1993). Moreover, AGP has found to potentiate the effect of suboptimal concentrations of LPS to induce IL-1β, IL-6 and TNF-α in peritoneal and alveolar macrophages (Boutten et al., 1992). Nakamura and collaborators presented evidence that monocytes stimulated with inflammatory cytokines produce AGP and suggested that high expression of AGP may potentially create a positive feedback loop for further production of IL-1β (Nakamura et al., 1993). The observation that AGP-induced secretion of TNFα can be inhibited by protein tyrosine kinase inhibitors led to the proposal that AGP involves tyrosine kinase signalling pathway (Su et al., 1999). This is in line with the finding that AGP binds to chemokine receptor CCR5 on macrophages and signals via tyrosine kinases (Atemezem et al., 2001). In neutrophil models AGP interacts with lectin-like receptors (Siglecs), Siglec-5 and/or Siglec-14, directly induces an intracellular calcium rise and regulates expression of L-selectin (Gunnarsson et al., 2007).

Recently, it has been reported that AGP up-regulates the expression of the Hb scavenger receptor CD163 on monocytic cells in vitro (Komori et al., 2012). In vivo, in the phenylhydrazine-induced hemolysis mice model AGP induced CD163 expression with a subsequent increase in Hb clearance and reduced oxidative stress. The effect of AGP on CD163 expression seems to be indirect and mediated by the IL-6 and IL-10, known inducers of CD163. According to Komori and co-workers AGP induces CD163 expression via the TLR4/CD14 pathway (Komori et al., 2012).

Taken together AGP seems to exhibit both pro- and anti-inflammatory effects. The resulting net function of AGP most likely depends on contextual factors, e.g. interacting cell type, additional stimuli, inflammatory status of the host.


9. C-reactive protein

Human C-reactive protein (CRP) belongs to a family of pentraxins (Myles et al., 1990) and is composed of five identical 23 kDa subunits (protomers), linked together non-covalently to form pentameric CRP. The liver is the main source for circulating CRP. Hepatic secretion of CRP is primarily regulated by IL-6 and IL-1 (Weinhold et al., 1997; Zhang et al., 1995). Plasma CRP is a highly dynamic protein with a concentration range from 0.05 to 500 µg/ml (Shine et al., 1981; Pepys & Hirschfield, 2003). Plasma CRP levels rise up to 10.000-fold in response to acute tissue injury or inflammation and decline rapidly due to a relatively short half-life (about 19 hours) (Macintyre et al., 1982; Claus et al., 1976; Vigushin et al., 1993). Cardiovascular disease is correlated to chronic inflammation and serum CRP above 3 μg/ml is a good predictive of increased risk for the disease (Black et al., 2004).

Both in vitro and in vivo CRP exists in a monomeric form (mCRP) with a molecular weight of 23 kDa, too (Taylor & van den Berg, 2007). The pentameric native form of CRP (nCRP) is usually found in the plasma whereas the momomeric form of CRP (mCRP) is present in tissues and at sites of inflammation (Diehl et al., 2000; Potempa et al., 1987; Rees et al., 1988). pCRP also undergoes conformational rearrangement in the absence of calcium and dissociates into mCRP (Eisenhardt et al., 2009). The modified CRP isoform is generated in vivo when pCRP binds to damaged membrane surfaces such as activated platelets, apoptotic microparticles (Habersberger et al., 2012), liposomes containing lysophosphatidylcholine (Volanakis & Narkates, 1981), and oxidized but not native low-density lipoprotein (Chang et al., 2002). Modified CRP displays an antigenicity that is distinct from pCRP. In fact, modified CRP may exist as aggregates of mCRP on cell membrane surfaces (Ji et al., 2007).

One critical function of modified CRP is binding to C1q and activation of the immune system’s complement cascade (Ji et al., 2006). In addition to its roles in the regulation of classical and alternative complement pathways, CRP has been shown to interact with ficolin-2 (Ng et al., 2007). Recent study has shown that infection-induced local inflammatory conditions trigger a strong interaction between CRP and ficolin-2; this elicits complement amplification and enhances antimicrobial activation of the classical and lectin pathways (Zhang et al., 2009).

Despite evidence that modified CRP is more strongly associated with inflammation (Zouki et al., 2001) current CRP diagnostics are unable to distinguish between the common isoforms.

Taken together, physiological function of CRP is not fully understood. The most reproducible observations indicate that CRP contributes to innate immunity against bacterial infections like pneumococci (Horowitz et al., 1987). Experimental data provide evidence that transgenic mice over-expressing human CRP are more resistant to Pneumococci sepsis than wild-type mice (Szalai et al., 1995). Indeed, CRP is expressed by respiratory epithelial cells and CRP concentrations in secretions from both inflamed and non-inflamed human respiratory tract are sufficiently high for an antimicrobial effect. This suggests that CRP is involved in the bacterial clearance in the respiratory tract (Gould & Weiser, 2001).

Recent findings lend experimental support to the hypothesis that biological activities of CRP might be dependent on both, its molecular form and the property to interact with plasma membrane lipid microdomains (Ji et al., 2009).

For example, CRP and two CRP derived peptides, CRP(174-185) and CRP(201-206), but not peptide CRP(77-82) are capable of diminishing attachment of human neutrophils to LPS-stimulated human endothelial cells and consequently limiting leukocyte traffic into inflamed tissues (Zouki et al., 1997). CRP as well as the two peptides rapidly downregulate the expression of L-selectin on the neutrophil surface.

In summary, CRP is used as an indicator of disease outcome and to monitor the disease course. CRP is measured objectively and affordably in clinical practice worldwide.


10. Conclusions

In this chapter we have shown that AAT, only one among many APPs, holds tremendous potential as an anti-inflammatory and immuno-modulatory protein.

Several in vitro and in vivo studies have been published in which a specific APP switched the pro-inflammatory to the anti-inflammatory pathways necessary for the resolution of inflammation. Although the physiological roles of APPs are not completely understood, existing findings provide evidence that APPs act on a variety of cells involved in early and late stages of inflammation and that their effects are time, concentration and molecular conformation-dependent. It cannot be excluded that these proteins may have more common characteristics and biological effects, however the lack of high quality purified endotoxin or other contaminant free proteins limits current understanding.

The mechanisms of action for the APPs are still being investigated, however, there remain a number of challenges to face in the development of APPs as a true anti-inflammatory therapeutic agents and diagnostic markers.


  1. 1. AbdullahMet al2012Pulmonary haptoglobin and CD163 are functional immunoregulatory elements in the human lung. Respiration 836173
  2. 2. AbdullahMet al2009Expression of the acute phase protein haptoglobin in human lung cancer and tumor-free lung tissues. Pathol Res Pract 205639647
  3. 3. AdamCet al1996Inhibition of neutrophil elastase by the alpha1-proteinase inhibitor-immunoglobulin A complex. FEBS Lett 385201204
  4. 4. Al-omariMet al2011Acute-phase protein alpha1-antitrypsin inhibits neutrophil calpain I and induces random migration. Mol Med 17865874
  5. 5. AldonyteRet al2008Endothelial alpha-1-antitrypsin attenuates cigarette smoke induced apoptosis in vitro. COPD 5153162
  6. 6. AmelinckxAet al2011Neutrophil Chemotaxis Induced by Molecular Modifications of Alpha-1 Antitrypsin (AAT) in COPD Subjects with and without AAT Deficiency. Am J Respir Crit Care Med 183, A2429.
  7. 7. ArredouaniMet al2003Haptoglobin directly affects T cells and suppresses T helper cell type 2 cytokine release. Immunology 108144151
  8. 8. ArredouaniM. Set al2005Haptoglobin dampens endotoxin-induced inflammatory effects both in vitro and in vivo. Immunology 114263271
  9. 9. AslehRet al2005In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease. Vasc Health Risk Manag 11928
  10. 10. AslehRet al2003Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Circ Res 9211931200
  11. 11. AtemezemAet al2001Human alpha1-acid glycoprotein binds to CCR5 expressed on the plasma membrane of human primary macrophages. Biochem J 356121128
  12. 12. BairdBet al1999How does the plasma membrane participate in cellular signaling by receptors for immunoglobulin E? Biophys Chem 82109119
  13. 13. BarraudBet al1996Effects of insulin, dexamethasone and cytokines on alpha 1-acid glycoprotein gene expression in primary cultures of normal rat hepatocytes. Inflammation 20191202
  14. 14. BaselerM. Wet al1983Purification of haptoglobin and its effects on lymphocyte and alveolar macrophage responses. Inflammation 7387400
  15. 15. BaumannHet al1990Distinct regulation of the interleukin-1 and interleukin-6 response elements of the rat haptoglobin gene in rat and human hepatoma cells. Mol Cell Biol 1059675976
  16. 16. BennettMet al1980Immunosuppression by human plasma alpha 1-acid glycoprotein: importance of the carbohydrate moiety. Proc Natl Acad Sci U S A 7761096113
  17. 17. BerginD. Aet al2010alpha-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. J Clin Invest 12042364250
  18. 18. BerkovaNet al1999TNF-induced haptoglobin release from human neutrophils: pivotal role of the TNF 55receptor. J Immunol 162, 6226-6232.
  19. 19. BermanM. Bet al1973Corneal ulceration and the serum antiproteases. I. Alpha 1-antitrypsin. Invest Ophthalmol 12759770
  20. 20. BlackSet al2004C-reactive Protein. J Biol Chem 2794848748490
  21. 21. BlanchardVet al2011N-glycosylation and biological activity of recombinant human alpha1-antitrypsin expressed in a novel human neuronal cell line. Biotechnol Bioeng 10821182128
  22. 22. BlancoIet al2011Efficacy of alpha1antitrypsin augmentation therapy in conditions other than pulmonary emphysema. Orphanet J Rare Dis 6, 14.
  23. 23. BorregaardNet al1992Stimulus-dependent secretion of plasma proteins from human neutrophils. J Clin Invest 908696
  24. 24. BoscoDet al2005Expression and secretion of alpha1-proteinase inhibitor are regulated by proinflammatory cytokines in human pancreatic islet cells. Diabetologia 4815231533
  25. 25. BoskovicGet al1997Retinol and retinaldehyde specifically increase alpha1proteinase inhibitor in the human cornea. Biochem J 322 ( Pt 3), 751-756.
  26. 26. BoskovicGet al1998Local control of alpha1-proteinase inhibitor levels: regulation of alpha1-proteinase inhibitor in the human cornea by growth factors and cytokines. Biochim Biophys Acta 14033746
  27. 27. BouttenAet al1992Alpha 1-acid glycoprotein potentiates lipopolysaccharide-induced secretion of interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha by human monocytes and alveolar and peritoneal macrophages. Eur J Immunol 2226872695
  28. 28. BouttenAet al1998Oncostatin M is a potent stimulator of alpha1-antitrypsin secretion in lung epithelial cells: modulation by transforming growth factor-beta and interferon-gamma. Am J Respir Cell Mol Biol 18511520
  29. 29. BowlusC. Let al2005Factors associated with advanced liver disease in adults with alpha1-antitrypsin deficiency. Clin Gastroenterol Hepatol 3390396
  30. 30. ChangM. Ket al2002C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: Phosphorylcholine of oxidized phospholipids. Proc Natl Acad Sci U S A 991304313048
  31. 31. ChenH. Cet al2006Tumor necrosis factor-alpha induces caspase-independent cell death in human neutrophils via reactive oxidants and associated with calpain activity. J Biomed Sci 13261273
  32. 32. ChiuK. Met al1977Interactions of alpha1-acid glycoprotein with the immune system. I. Purification and effects upon lymphocyte responsiveness. Immunology 329971005
  33. 33. ChowanadisaiWet al2002Alpha(1)-antitrypsin and antichymotrypsin in human milk: origin, concentrations, and stability. Am J Clin Nutr 76828833
  34. 34. ChurgAet al2001Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects. Lab Invest 8111191131
  35. 35. ClausD. Ret al1976Radioimmunoassay of human C-reactive protein and levels in normal sera. J Lab Clin Med 87120128
  36. 36. ClemmensenS. Net al2011Alpha-1-antitrypsin is produced by human neutrophil granulocytes and their precursors and liberated during granule exocytosis. Eur J Haematol 86517530
  37. 37. ColomboSet al2006Orosomucoid (alpha1-acid glycoprotein) plasma concentration and genetic variants: effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation. Clin Pharmacol Ther 80307318
  38. 38. CongoteL. Fet al2008Comparison of the effects of serpin A1, a recombinant serpin A1-IGF chimera and serpin A1 C-terminal peptide on wound healing. Peptides 293946
  39. 39. CostelloM. Jet al1984Inhibition of neutrophil activation by alpha1-acid glycoprotein. Clin Exp Immunol 55465472
  40. 40. CrestaniBet al1998Inducible expression of the alpha1-acid glycoprotein by rat and human type II alveolar epithelial cells. J Immunol 16045964605
  41. 41. CurielD. Tet al1989Serum alpha 1-antitrypsin deficiency associated with the common S-type (Glu264----Val) mutation results from intracellular degradation of alpha 1-antitrypsin prior to secretion. J Biol Chem 2641047710486
  42. 42. CurryF. Eet al1989Modulation of microvessel wall charge by plasma glycoprotein orosomucoid. Am J Physiol 257, H13541359
  43. 43. DaemenM. Aet al2000Functional protection by acute phase proteins alpha(1)-acid glycoprotein and alpha(1)-antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation. Circulation 10214201426
  44. 44. DiehlE. Eet al2000Immunohistochemical localization of modified C-reactive protein antigen in normal vascular tissue. Am J Med Sci 3197983
  45. 45. DirienzoWet al1987Alpha 1-acid glycoprotein (alpha 1-AGP) on the membrane of human lymphocytes: possible involvement in cellular activation. Immunol Lett 15167170
  46. 46. EhrensteinM. Ret al2005Statins for atherosclerosis--as good as it gets? N Engl J Med 3527375
  47. 47. EisenhardtS. Uet al2009Monomeric C-reactive protein generation on activated platelets: the missing link between inflammation and atherothrombotic risk. Trends Cardiovasc Med 19232237
  48. 48. ElgS. Aet al1997Alpha-1 acid glycoprotein is an immunosuppressive factor found in ascites from ovaria carcinoma. Cancer 8014481456
  49. 49. EsnaultV. Let al1997Alpha-1-antitrypsin phenotyping in ANCA-associated diseases: one of several arguments for protease/antiprotease imbalance in systemic vasculitis. Exp Clin Immunogenet 14206213
  50. 50. EsnaultV. Let al1993Alpha 1-antitrypsin genetic polymorphism in ANCA-positive systemic vasculitis. Kidney Int 4313291332
  51. 51. FaustDet al2001Butyrate and the cytokine-induced alpha1-proteinase inhibitor release in intestinal epithelial cells. Eur J Clin Invest 3110601063
  52. 52. FinottiPet al2004A heat shock protein70 fusion protein with alpha1-antitrypsin in plasma of type 1 diabetic subjects. Biochem Biophys Res Commun 315297305
  53. 53. FournierTet al1999Inducible expression and regulation of the alpha 1-acid glycoprotein gene by alveolar macrophages: prostaglandin E2 and cyclic AMP act as new positive stimuli. J Immunol 16328832890
  54. 54. FournierTet al2000Alpha-1-acid glycoprotein. Biochim Biophys Acta 1482157171
  55. 55. FregoneseLet al2008Alpha-1 antitrypsin Null mutations and severity of emphysema. Respir Med 102876884
  56. 56. FureyN. Let al1996Treatment of alpha-1antitrypsin deficiency, massive edema, and panniculitis with alpha-1 protease inhibitor. Ann Intern Med 125, 699.
  57. 57. GahmbergC. Get al1978Leukocyte surface origin of human alpha1-acid glycoprotein (orosomucoid). J Exp Med 148507521
  58. 58. GeboesKet al1982Morphological identification of alpha-I-antitrypsin in the human small intestine. Histopathology 65560
  59. 59. GettinsP. G2002Serpin structure, mechanism, and function. Chem Rev 10247514804
  60. 60. GolubTet al2004Spatial and temporal control of signaling through lipid rafts. Curr Opin Neurobiol 14542550
  61. 61. GombosIet al2006Cholesterol and sphingolipids as lipid organizers of the immune cells’ plasma membrane: their impact on the functions of MHC molecules, effector T-lymphocytes and T-cell death. Immunol Lett 1045969
  62. 62. GouldJ. Met al2001Expression of C-reactive protein in the human respiratory tract. Infect Immun 6917471754
  63. 63. GraversenJ. Het al2002CD163: a signal receptor scavenging haptoglobin-hemoglobin complexes from plasma. Int J Biochem Cell Biol 34309314
  64. 64. GraziadeiIet al1994The acute-phase protein alpha 1-antitrypsin inhibits growth and proliferation of human early erythroid progenitor cells (burst-forming units-erythroid) and of human erythroleukemic cells (K562) in vitro by interfering with transferrin iron uptake. Blood 83260268
  65. 65. GraziadeiIet al1997Unidirectional upregulation of the synthesis of the major iron proteins, transferrin-receptor and ferritin, in HepG2 cells by the acute-phase protein alpha1-antitrypsin. J Hepatol 27716725
  66. 66. GrimsteinCet al2010Combination of alpha-1 antitrypsin and doxycycline suppresses collagen-induced arthritis. J Gene Med 123544
  67. 67. GrossBet al2009New Findings in PiZZ alpha1-antitrypsin deficiency-related panniculitis. Demonstration of skin polymers and high dosing requirements of intravenous augmentation therapy. Dermatology 218370375
  68. 68. GuettaJet al2007Haptoglobin genotype modulates the balance of Th1/Th2 cytokines produced by macrophages exposed to free hemoglobin. Atherosclerosis 1914853
  69. 69. GunnarssonPet al2007The acute-phase protein alpha 1-acid glycoprotein (AGP) induces rises in cytosolic Ca2+ in neutrophil granulocytes via sialic acid binding immunoglobulin-like lectins (siglecs). FASEB J 2140594069
  70. 70. HabersbergerJet al2012Circulating microparticles generate and transport monomeric C-reactive protein in patients with myocardial infarction. Cardiovasc Res
  71. 71. HallPet al1986Functional activities and nonenzymatic glycosylation of plasma proteinase inhibitors in diabetes. Clin Chim Acta 1605562
  72. 72. HardingCet al1983Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97329339
  73. 73. HochepiedTet al2003Alpha(1)-acid glycoprotein: an acute phase protein with inflammatory and immunomodulating properties. Cytokine Growth Factor Rev 142534
  74. 74. HorowitzJet al1987Blood clearance of Streptococcus pneumoniae by C-reactive protein. J Immunol 13825982603
  75. 75. HuangC. M2004Comparative proteomic analysis of human whole saliva. Arch Oral Biol 49951962
  76. 76. HubbardR. Cet al1988Alpha-1-antitrypsin augmentation therapy for alpha-1-antitrypsin deficiency. Am J Med 845262
  77. 77. JanciauskieneS2001Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles. Biochim Biophys Acta 1535221235
  78. 78. JanciauskieneSet al1993In vitro complex formation between cholesterol and alpha 1-proteinase inhibitor. FEBS Lett 316269272
  79. 79. JanciauskieneSet al2004Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by alpha1-antitrypsin. Biochem Biophys Res Commun 321592600
  80. 80. JanciauskieneSet al2010Plasma levels of TIMP-1 are higher in 34year-old individuals with severe alpha1-antitrypsin deficiency. Thorax 65, 937.
  81. 81. JanciauskieneSet al1996Immunochemical and functional properties of biliary alpha-1-antitrypsin. Scand J Clin Lab Invest 56597608
  82. 82. JanciauskieneS. Met al2011The discovery of alpha1-antitrypsin and its role in health and disease. Respir Med 10511291139
  83. 83. JanesP. Wet al2000The role of lipid rafts in T cell antigen receptor (TCR) signalling. Semin Immunol 122334
  84. 84. JiS. Ret al2009Monomeric C-reactive protein activates endothelial cells via interaction with lipid raft microdomains. FASEB J 2318061816
  85. 85. JiS. Ret al2006Effect of modified C-reactive protein on complement activation: a possible complement regulatory role of modified or monomeric C-reactive protein in atherosclerotic lesions. Arterioscler Thromb Vasc Biol 26935941
  86. 86. JiS. Ret al2007Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP(m). FASEB J 21284294
  87. 87. JieZet al2003Protective effects of alpha 1-antitrypsin on acute lung injury in rabbits induced by endotoxin. Chin Med J (Engl) 11616781682
  88. 88. JohanssonBet al2001Alpha-1-antitrypsin is present in the specific granules of human eosinophilic granulocytes. Clin Exp Allergy 31379386
  89. 89. KalshekerNet al2002Gene regulation of the serine proteinase inhibitors alpha1-antitrypsin and alpha1-antichymotrypsin. Biochem Soc Trans 309398
  90. 90. KnoellD. Let al1998Alpha 1-antitrypsin and protease complexation is induced by lipopolysaccharide, interleukin-1beta, and tumor necrosis factor-alpha in monocytes. Am J Respir Crit Care Med 157246255
  91. 91. KokK. Fet al2007Heterozygous alpha-I antitrypsin deficiency as a co-factor in the development of chronic liver disease: a review. Neth J Med 65160166
  92. 92. KomoriHet al2012alpha1-Acid Glycoprotein Up-regulates CD163 via TLR4/CD14 Protein Pathway: POSSIBLE PROTECTION AGAINST HEMOLYSIS-INDUCED OXIDATIVE STRESS. J Biol Chem 2873068830700
  93. 93. KremerJ. Met al1988Drug binding to human alpha-1-acid glycoprotein in health and disease. Pharmacol Rev 40147
  94. 94. KristiansenMet al2001Identification of the haemoglobin scavenger receptor. Nature 409198201
  95. 95. LaineEet al1990Modulation of human polymorphonuclear neutrophil functions by alpha 1-acid glycoprotein. Inflammation 1419
  96. 96. LaurellC. Bet al1975Thiol-disulfide interchange in the binding of bence jones proteins to alpha-antitrypsin, prealbumin, and albumin. J Exp Med 141453465
  97. 97. LevyA. Pet al2010Haptoglobin: basic and clinical aspects. Antioxid Redox Signal 12293304
  98. 98. LewisE. C2012Expanding the Clinical Indications for Alpha-1Antitrypsin Therapy. Mol Med
  99. 99. LewisE. Cet al2008alpha1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice. Proc Natl Acad Sci U S A 1051623616241
  100. 100. LewisE. Cet al2005Alpha1-antitrypsin monotherapy prolongs islet allograft survival in mice. Proc Natl Acad Sci U S A 1021215312158
  101. 101. LogdbergLet al2000Immunocalins: a lipocalin subfamily that modulates immune and inflammatory responses. Biochim Biophys Acta 1482284297
  102. 102. LokutaM. Aet al2003Calpain regulates neutrophil chemotaxis. Proc Natl Acad Sci U S A 10040064011
  103. 103. MacintyreS. Set al1982Biosynthesis of C-reactive protein. Ann N Y Acad Sci 3897687
  104. 104. MarcondesA. Met al2011Inhibition of IL-32 activation by alpha-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model. Blood 11850315039
  105. 105. MarinkovicSet al1990Structure, hormonal regulation, and identification of the interleukin-6- and dexamethasone-responsive element of the rat haptoglobin gene. Mol Cell Biol 1015731583
  106. 106. MarquezLet al2012Effects of haptoglobin polymorphisms and deficiency on susceptibility to inflammatory bowel disease and on severity of murine colitis. Gut 61528534
  107. 107. Martinez CorderoE, et al. (2008Alpha-1-acid glycoprotein, its local production and immunopathological participation in experimental pulmonary tuberculosis. Tuberculosis (Edinb) 88203211
  108. 108. MashibaSet al2001In vivo complex formation of oxidized alpha(1)-antitrypsin and LDL. Arterioscler Thromb Vasc Biol 2118011808
  109. 109. MejdoubiNet al1999Growth hormone inhibits rat liver alpha-1-acid glycoprotein gene expression in vivo and in vitro. Hepatology 29186194
  110. 110. MohankaMet al2012A review of augmentation therapy for alpha-1 antitrypsin deficiency. Expert Opin Biol Ther 12685700
  111. 111. MontanelliAet al2002Alpha-1-antitrypsin deficiency and nephropathy. Nephron 90114115
  112. 112. MuchitschE. Met al1998Effects of alpha 1-acid glycoprotein in different rodent models of shock. Fundam Clin Pharmacol 12173181
  113. 113. MuchitschE. Met al1996In vivo effect of alpha 1-acid glycoprotein on experimentally enhanced capillary permeability in guinea-pig skin. Arch Int Pharmacodyn Ther 331313321
  114. 114. MurakamiTet al1993Elevation of factor XIa-alpha 1-antitrypsin complex levels in NIDDM patients with diabetic nephropathy. Diabetes 42233238
  115. 115. MylesD. Aet al1990Rotation function studies of human C-reactive protein. J Mol Biol 216491496
  116. 116. NakamuraTet al1993Alpha 1-acid glycoprotein expression in human leukocytes: possible correlation between alpha 1-acid glycoprotein and inflammatory cytokines in rheumatoid arthritis. Inflammation 173345
  117. 117. NevoS. Set al1968Association between response to typhoid vaccination and known genetic markers. Am J Hum Genet 20461469
  118. 118. NgP. Met al2007C-reactive protein collaborates with plasma lectins to boost immune response against bacteria. EMBO J 2634313440
  119. 119. NitaIet al2005Prolastin, a pharmaceutical preparation of purified human alpha1antitrypsin, blocks endotoxin-mediated cytokine release. Respir Res 6, 12.
  120. 120. ODonoghueDJ, et al1993Alpha-1-proteinase inhibitor and pulmonary haemorrhage in systemic vasculitis. Adv Exp Med Biol 336331335
  121. 121. ORiordanK, et al1997alpha 1-antitrypsin deficiency-associated panniculitis: resolution with intravenous alpha 1-antitrypsin administration and liver transplantation. Transplantation 63480482
  122. 122. OhS. Ket al1990Specific binding of haptoglobin to human neutrophils and its functional consequences. J Leukoc Biol 47142148
  123. 123. OtterbeinL. Eet al2003Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol 24449455
  124. 124. OzeriEet al2012alpha-1 antitrypsin promotes semimature, IL-10-producing and readily migrating tolerogenic dendritic cells. J Immunol 189146153
  125. 125. PaakkoPet al1996Activated neutrophils secrete stored alpha 1-antitrypsin. Am J Respir Crit Care Med 15418291833
  126. 126. ParraM. Det al2006Porcine acute phase protein concentrations in different diseases in field conditions. J Vet Med B Infect Dis Vet Public Health 53488493
  127. 127. PepysM. Bet al2003C-reactive protein: a critical update. J Clin Invest 11118051812
  128. 128. PerlmutterD. Het al1990Endocytosis and degradation of alpha 1-antitrypsin-protease complexes is mediated by the serpin-enzyme complex (SEC) receptor. J Biol Chem 2651671316716
  129. 129. PerlmutterD. Het al1985The cellular defect in alpha 1-proteinase inhibitor (alpha 1-PI) deficiency is expressed in human monocytes and in Xenopus oocytes injected with human liver mRNA. Proc Natl Acad Sci U S A 8269186921
  130. 130. PerlmutterD. Het al1988Distinct and additive effects of elastase and endotoxin on expression of alpha 1 proteinase inhibitor in mononuclear phagocytes. J Biol Chem 2631649916503
  131. 131. PerlmutterD. Het al1988Elastase regulates the synthesis of its inhibitor, alpha 1-proteinase inhibitor, and exaggerates the defect in homozygous PiZZ alpha 1 PI deficiency. J Clin Invest 8117741780
  132. 132. PetracheIet al2006alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am J Pathol 16911551166
  133. 133. PiliangM. Pet al2008Women with ulcerating, painful skin lesions. Cleve Clin J Med 75, 414, 418, 422.
  134. 134. PollerWet al1995Differential recognition of alpha 1-antitrypsin-elastase and alpha 1-antichymotrypsin-cathepsin G complexes by the low density lipoprotein receptor-related protein. J Biol Chem 27028412845
  135. 135. PoortmansJet al1968Quantitative immunological determination of 12 plasma proteins excreted in human urine collected before and after exercise. J Clin Invest 47386393
  136. 136. PosOet al1990Con A-nonreactive human alpha 1-acid glycoprotein (AGP) is more effective in modulation of lymphocyte proliferation than Con A-reactive AGP serum variants. Inflammation 14133141
  137. 137. PotempaL. Aet al1987Expression, detection and assay of a neoantigen (Neo-CRP) associated with a free, human C-reactive protein subunit. Mol Immunol 24531541
  138. 138. PriesA. Ret al2000The endothelial surface layer. Pflugers Arch 440653666
  139. 139. PropstTet al1994Alpha-1-antitrypsin deficiency and liver disease. Dig Dis 12139149
  140. 140. RahmanM. Met al2008Alpha(1)-acid glycoprotein is contained in bovine neutrophil granules and released after activation. Vet Immunol Immunopathol 1257181
  141. 141. RayM. Bet al1982Alpha-1-antitrypsin immunoreactivity in gastric carcinoid. Histopathology 6289297
  142. 142. RaynesJ. Get al1991Acute-phase protein synthesis in human hepatoma cells: differential regulation of serum amyloid A (SAA) and haptoglobin by interleukin-1 and interleukin-6. Clin Exp Immunol 83488491
  143. 143. ReesR. Fet al1988Expression of a C-reactive protein neoantigen (neo-CRP) in inflamed rabbit liver and muscle. Clin Immunol Immunopathol 4895107
  144. 144. RossbacherJet al1999Inhibitory effect of haptoglobin on granulocyte chemotaxis, phagocytosis and bactericidal activity. Scand J Immunol 50399404
  145. 145. SamakRet al1982Immunosuppressive effect of acute-phase reactant proteins in vitro and its relevance to cancer. Cancer Immunol Immunother 133843
  146. 146. SchaerD. Jet al2006CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin. Blood 107373380
  147. 147. SchmidKet al1977The carbohydrate units of human plasma alpha1-acid glycoprotein. Biochim Biophys Acta 492291302
  148. 148. ShinS. Yet al2011Changes of Alpha1-Antitrypsin Levels in Allergen-induced Nasal Inflammation. Clin Exp Otorhinolaryngol 43339
  149. 149. ShineBet al1981Solid phase radioimmunoassays for human C-reactive protein. Clin Chim Acta 1171323
  150. 150. SiekmeierR2010Lung deposition of inhaled alpha-1-proteinase inhibitor (alpha 1-PI)- problems and experience of alpha1-PI inhalation therapy in patients with hereditary alpha1-PI deficiency and cystic fibrosis. Eur J Med Res 15 Suppl 2164174
  151. 151. SimonsKet al2000Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 13139
  152. 152. SiricaA. Eet al1979Fetal phenotypic expression by adult rat hepatocytes on collagen gel/nylon meshes. Proc Natl Acad Sci U S A 76283287
  153. 153. SlaughterNet al2003The flotillins are integral membrane proteins in lipid rafts that contain TCR-associated signaling components: implications for T-cell activation. Clin Immunol 108138151
  154. 154. SmithK. Cet al1989Clinical and pathologic correlations in 96 patients with panniculitis, including 15 patients with deficient levels of alpha 1-antitrypsin. J Am Acad Dermatol 2111921196
  155. 155. SmolarczykKet al2005Function-stabilizing mechanism of plasminogen activator inhibitor type 1 induced upon binding to alpha1-acid glycoprotein. Biochemistry 441238412390
  156. 156. SohrabSet al2009Mechanism of alpha-1 antitrypsin endocytosis by lung endothelium. FASEB J 2331493158
  157. 157. SorenssonJet al1999Human endothelial cells produce orosomucoid, an important component of the capillary barrier. Am J Physiol 276, H530534
  158. 158. StockleyR. Aet al2010Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. Respir Res 11, 136.
  159. 159. StocksB. Bet al2012Early Hydrophobic Collapse of alpha(1)-Antitrypsin Facilitates Formation of a Metastable State: Insights from Oxidative Labeling and Mass Spectrometry. J Mol Biol
  160. 160. SuS. Jet al1999Alpha 1-acid glycoprotein-induced tumor necrosis factor-alpha secretion of human monocytes is enhanced by serum binding proteins and depends on protein tyrosine kinase activation. Immunopharmacology 412129
  161. 161. SuS. Jet al1996Effects of alpha 1-acid glycoprotein on tissue factor expression and tumor necrosis factor secretion in human monocytes. Immunopharmacology 34139145
  162. 162. SubramaniyamDet al2006C-36 peptide, a degradation product of alpha1-antitrypsin, modulates human monocyte activation through LPS signaling pathways. Int J Biochem Cell Biol 38563575
  163. 163. SubramaniyamDet al2008TNF-alpha-induced self expression in human lung endothelial cells is inhibited by native and oxidized alpha1-antitrypsin. Int J Biochem Cell Biol 40258271
  164. 164. SubramaniyamDet al2010Cholesterol rich lipid raft microdomains are gateway for acute phase protein, SERPINA1. Int J Biochem Cell Biol 4215621570
  165. 165. SzalaiA. Jet al1995Human C-reactive protein is protective against fatal Streptococcus pneumoniae infection in transgenic mice. J Immunol 15525572563
  166. 166. TawaraIet al2012Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. Proc Natl Acad Sci U S A 109564569
  167. 167. TaylorK. Eet al2007Structural and functional comparison of native pentameric, denatured monomeric and biotinylated C-reactive protein. Immunology 120404411
  168. 168. Theilgaard-monchKet al2005Highly glycosylated alpha1-acid glycoprotein is synthesized in myelocytes, stored in secondary granules, and released by activated neutrophils. J Leukoc Biol 78462470
  169. 169. TilgHet al1993Antiinflammatory properties of hepatic acute phase proteins: preferential induction of interleukin 1 (IL-1) receptor antagonist over IL-1 beta synthesis by human peripheral blood mononuclear cells. J Exp Med 17816291636
  170. 170. TuderR. Met al2010Lung disease associated with alpha1-antitrypsin deficiency. Proc Am Thorac Soc 7381386
  171. 171. Van MolleWet al1999Activation of caspases in lethal experimental hepatitis and prevention by acute phase proteins. J Immunol 16352355241
  172. 172. VigushinD. Met al1993Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. J Clin Invest 9113511357
  173. 173. VolanakisJ. Eet al1981Interaction of C-reactive protein with artificial phosphatidylcholine bilayers and complement. J Immunol 12618201825
  174. 174. WagnerLet al1996Haptoglobin phenotyping by newly developed monoclonal antibodies. Demonstration of haptoglobin uptake into peripheral blood neutrophils and monocytes. J Immunol 15619891996
  175. 175. WarnockD. Eet al1993Determination of plasma membrane lipid mass and composition in cultured Chinese hamster ovary cells using high gradient magnetic affinity chromatography. J Biol Chem 2681014510153
  176. 176. WeinholdBet al1997Interleukin-6 is necessary, but not sufficient, for induction of the humanC-reactive protein gene in vivo. Biochem J 325 ( Pt 3), 617-621.
  177. 177. WiemerA. Jet al2010Calpain inhibition impairs TNF-alpha-mediated neutrophil adhesion, arrest and oxidative burst. Mol Immunol 47894902
  178. 178. WuLet al2005The low-density lipoprotein receptor-related protein-1 associates transiently with lipid rafts. J Cell Biochem 9610211033
  179. 179. YoonI. Set al2007Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway. FASEB J 2127422752
  180. 180. YoshiokaMet al2002Regulation of haptoglobin secretion by recombinant bovine cytokines in primary cultured bovine hepatocytes. Domest Anim Endocrinol 23425433
  181. 181. YuS. Jet al1999Attenuation of haptoglobin gene expression by TGFbeta requires the MAP kinase pathway. Biochem Biophys Res Commun 259544549
  182. 182. ZhangBet al2007Alpha1-antitrypsin protects beta-cells from apoptosis. Diabetes 5613161323
  183. 183. ZhangDet al1995The effect of interleukin-1 on C-reactive protein expression in Hep3B cells is exerted at the transcriptional level. Biochem J 310 ( Pt 1), 143-148.
  184. 184. ZhangJet al2009Local inflammation induces complement crosstalk which amplifies the antimicrobial response. PLoS Pathog 5, e1000282.
  185. 185. ZhuDet al2006Lipid rafts serve as a signaling platform for nicotinic acetylcholine receptor clustering. J Neurosci 2648414851
  186. 186. ZoukiCet al1997Prevention of In vitro neutrophil adhesion to endothelial cells through shedding of L-selectin by C-reactive protein and peptides derived from C-reactive protein. J Clin Invest 100522529
  187. 187. ZoukiCet al2001Loss of pentameric symmetry of C-reactive protein is associated with promotion of neutrophil-endothelial cell adhesion. J Immunol 16753555361

Written By

S. Janciauskiene, S. Wrenger and T. Welte

Submitted: September 18th, 2012 Published: July 24th, 2013