Elsevier

Clinical Immunology

Volume 117, Issue 2, November 2005, Pages 104-111
Clinical Immunology

Short Analytical Review
C-reactive protein: Ligands, receptors and role in inflammation

https://doi.org/10.1016/j.clim.2005.08.004Get rights and content

Abstract

C-reactive protein (CRP) is the prototypical acute phase serum protein, rising rapidly in response to inflammation. CRP binds to phosphocholine (PC) and related molecules on microorganisms and plays an important role in host defense. However, a more important role may be the binding of CRP to PC in damaged membranes. CRP increases clearance of apoptotic cells, binds to nuclear antigens and by masking autoantigens from the immune system or enhancing their clearance, CRP may prevent autoimmunity. CRP binds to both the stimulatory receptors, FcγRI and FcγRIIa, increasing phagocytosis and the release of inflammatory cytokines; and to the inhibitory receptor, FcγRIIb, blocking activating signals. We have shown that, in two animal models of systemic lupus erythematosus (SLE), the (NZB × NZW)F1 mouse and the MRL/lpr mouse, a single injection of CRP before onset of proteinuria delayed disease development and late treatment reversed proteinuria. Thus, in these models, CRP plays an anti-inflammatory role.

Introduction

C-reactive protein (CRP) is the prototypical acute phase protein in humans. Tillet and Francis discovered CRP over 70 years ago in the blood of patients with Streptococcus pneumoniae infection [1], as a substance that precipitated the “C” polysaccharide of the cell wall of the pneumococcus and they called it C-reactive substance, which was later changed to C-reactive protein [2]. The acute phase nature of CRP was observed in these early studies. It was undetectable in normal blood and appeared at high concentrations very early during the course of the infection. If the patient recovered, the substance again became undetectable. This substance was also found in the blood of patients acutely ill with other febrile diseases, such as hemolytic streptococcus infection, rheumatic fever and staphylococcus infection. Clinically, CRP has been used to detect acute infections and to assess the response to treatment. It has also been used to evaluate the inflammatory response in chronic diseases, such as vasculitis and rheumatoid arthritis. In addition, CRP levels slightly above normal have been put forth as an indicator of mild inflammation associated with atherosclerotic vascular disease [3].

Section snippets

Synthesis

CRP is primarily made in the liver [4] in response to IL-6, and this synthesis is enhanced synergistically by IL-1β [5]. IL-1β enhances IL-6 induction through NF-κB p50 and p65 [6]. IL-6 induction is mediated by transcription factors STAT3 acting through a response element at position −108 [7], and C/EBPβ acting through response elements at positions −52 [8] and −219 [9]. Transcription is also controlled through E-box elements [10] in the promoter at positions −412 to −407 (E-box1) and −394 to

Structure

CRP is a member of the pentraxin protein family and consists of a cyclical arrangement of 5 identical non-covalently bound subunits (protomers). The crystal structure has been determined with binding sites for 2 calcium ions and one phosphocholine (PC) molecule per protomer on the B face [18], [19], and binding sites for C1q and Fc receptors hypothesized to be on the A face. Two regions in IgG have been identified as important for binding to FcγRI, 234LLGGPS239 for human IgG1 (FLGGPS in IgG4)

Ligands

The most well characterized ligand of CRP is PC (Fig. 3) [18]. This interaction requires calcium and is responsible for the binding to several microorganisms including the C-polysaccharide of pneumococcus [24], the repeating phosphorylated disaccharide on Leishmania donovani [25] and the lipopolysaccaride of Hemophilus influenzae [26]. This activity has very ancient roots since a homologous protein can be found in the horseshoe crab, Limulus polyphemus, which has been in existence for 70

Complement activation

A very important property of CRP is the ability to bind C1q to activate the classical complement cascade. Activation of complement is a factor in the killing of microorganisms and mediates protection by CRP from pathogenic bacteria such as S. pneumoniae [41] and H. influenzae [26]. Complement activation by CRP differs from activation by antibody in that there is selective activation of early components without the formation of the membrane attack complex (MAC). CRP recruits factor H to the cell

Binding to receptors

The literature concerning the receptor for CRP on leukocytes was confusing for many years (reviewed in [46]). We were able to show specific binding of CRP using COS-7 cells transfected with plasmids expressing FcγRI [21]. This was confirmed by others using surface plasmon resonance [47] and they showed that CRP actually bound to FcγRI with a 3-fold higher affinity than IgG. This binding was inhibited by IgG1 but not by PC. Binding to FcγRI increased phagocytosis of erythrocytes opsonized with

Protection from bacterial infection

CRP was first shown to be protective from bacterial infection in an in vivo mouse model of S. pneumoniae infection by our laboratory [41]. This has been confirmed by others also using passive inoculation [60] and in transgenic animals [61]. The mechanism is presumably through binding of CRP to the pneumococcal C-polysaccharide and opsonization of the bacteria for phagocytosis and thereby killing. The opsonization of S. pneumoniae, in the presence of CRP, primarily activates the classical

Anti-inflammatory effects

Humans and mice differ significantly in the control of CRP synthesis. In humans, CRP is the prototypical acute phase protein, while in mice, it is expressed constitutively at low levels and increases only slightly during the acute-phase response [67]. Therefore, to study the effect of CRP in the mouse requires the addition of CRP from another species, either passively or through a transgene. Samols and colleagues [68] developed a transgenic mouse expressing rabbit CRP under control of the rat

Conclusion

During the acute phase, where CRP plays an anti-inflammatory role, CRP is produced very rapidly and at high levels. In contrast, CRP levels slightly higher than normal have increasingly been used as an indicator of inflammation associated with cardiovascular disease. However, the same factors that are shown to increase CRP levels, i.e., age, obesity, smoking and diet, are also risk factors for cardiovascular disease. There is also a genetic influence, not only on CRP levels, but in addition,

Acknowledgments

This work was supported by the Department of Veterans Affairs and NIH grant AI-28358.

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