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C-reactive protein (CRP) is a member of the pentraxin family of proteins. These proteins are highly conserved over the course of evolution being present as far back as 250 million years ago. Mammalian pentraxins are characterized by the presence of five identical non-covalently linked subunits. Each subunit has a structurally conserved site for calcium-dependent ligand binding. The biological activities of the pentraxins established over many years include the ability to mediate opsonization for phagocytosis and complement activation. Pentraxins have an important role in protection from infection from pathogenic bacteria, and regulation of the inflammatory response. It was recognized early on that some of these functions are mediated by activation of the classical complement pathway through C1q. However, experimental evidence suggested that cellular receptors for pentraxins also play a role in phagocytosis. More recent experimental evidence indicates a direct link between pentraxins and Fc receptors. The Fc receptors were first identified as the major receptors for immunoglobulins. The avidity of the interaction between IgG complexes and Fc receptors is greatly enhanced when multivalent ligands interact with the IgG binding sites and activation of signaling pathways requires Fc receptor crosslinking. Human pentraxins bind and activate human and mouse IgG receptors, FcγRI and FcγRII, and the human IgA receptor, FcαRI. The affinities of the interactions between Fc receptors and pentraxins in solution and on cell surfaces are similar to antibody binding to low affinity Fc receptors. Crystallographic and mutagenesis studies have defined the structural features of these interactions and determined the stoichiometry of binding as one-to-one. Pentraxin aggregation or binding to multivalent ligands increases the avidity of binding and results in activation of these receptors for phagocytosis and cytokine synthesis. This review will discuss the structural and functional characteristics of pentraxin Fc receptor interactions and their implications for host defense and inflammation.

C-reactive protein (CRP) is the prototypic marker of inflammation and a strong predictor of cardiovascular events in humans. There are questions regarding the validity of the biological effects reported for CRP, in spite of adherence to rigorous control measures minimizing endotoxin [lipopolysaccharide (LPS)] contamination in these in vitro studies. In this study, we addressed the key question of endotoxin contamination in CRP preparations using Toll-like receptor 4 (TLR4) knockdown endothelial cells. Human aortic endothelial cells (HAECs) transfected with prevalidated TLR4 small interfering RNA (siRNA) and scrambled siRNA controls were challenged with pleural fluid-derived CRP or LPS for 12–16 h. Secreted interleukin-6 (IL-6), IL-1β, IL-8, and plasminogen activator inhibitor-1 (PAI-1) levels and endothelial Nitric oxide synthase (eNOS) activity were determined. TLR4 knockdown in HAECs significantly decreased LPS-induced IL-1β, IL-6, and IL-8, whereas the stimulatory effects of CRP were similar in both scrambled control and TLR4 knockdown cells. Furthermore, CRP significantly stimulated PAI-1 levels in both control and TLR4-transfected cells and inhibited eNOS activity, whereas LPS effects were negated in TLR4-transfected cells. The data presented cogently demonstrate and further confirm that the biological effects of CRP on HAECs are independent of LPS and thus are attributable to native protein per se. This is the first study to positively authenticate the significance of earlier in vitro reports on CRP biological effects.

C‐reactive protein (CRP) is an acute‐phase serum protein with binding reactivity to nuclear autoantigens and immunomodulatory function. The MRL/lpr mouse is an important model of human systemic lupus erythematosus (SLE). These mice develop high‐titer anti‐DNA antibodies and immune complex–mediated nephritis and exhibit progressive lymphadenopathy. The mortality rate among these mice is 50% by age 18–20 weeks; the most frequent cause of death is glomerulonephritis. The present study was undertaken to determine whether treatment of mice with CRP would affect the course of lupus nephritis.MRL/lpr mice were treated with a single 200‐μg injection of CRP at either age 6 weeks (before disease onset) or age 13 or 15 weeks (when proteinuria had reached high levels). Proteinuria was measured weekly, and levels of anti–double‐stranded DNA autoantibodies and blood urea nitrogen were determined monthly. Glomerular immune complex deposition and renal pathology were assessed in mice ages 15 weeks and 17 weeks.Early CRP treatment markedly delayed the onset of proteinuria and lymphadenopathy, increased survival, and reduced levels of autoantibodies to DNA. Treatment of mice with active disease reversed proteinuria and prolonged survival. Renal disease was decreased in CRP‐treated mice, with a marked suppression of glomerular pathology, tubular degeneration, and interstitial inflammation, which correlated with the decrease in proteinuria and azotemia.These findings demonstrate that systemic suppression of autoimmunity is initiated by a single injection of CRP. Long‐term maintenance of CRP‐mediated protection was reversed by injection of an anti‐CD25 monoclonal antibody but not by macrophage depletion, suggesting that disease suppression is maintained by CD25‐bearing T cells. [ABSTRACT FROM AUTHOR]

To examine the ability of injection of C‐reactive protein (CRP) to treat systemic lupus erythematosus (SLE) in the (NZB × NZW)F1 (NZB/NZW) mouse and to use a nephrotoxic nephritis (NTN) model to further examine the mechanism of this activity.NZB/NZW mice were given a single injection of 200 μg of CRP prior to disease onset or after the onset of high‐grade proteinuria. Mice were monitored weekly for proteinuria and monthly for anti–double‐stranded DNA (anti‐dsDNA) antibodies. NTN was induced by immunization with rabbit IgG followed by rabbit anti‐mouse glomerular basement membrane. Proteinuria was measured daily, and renal pathology was scored. CRP was injected at the time of disease induction or 9 days later.Treatment of NZB/NZW mice with CRP prior to disease onset delayed the onset of high‐grade proteinuria by 16 weeks (P < 0.0001) and prolonged survival by 13 weeks (P < 0.002). CRP treatment of NZB/NZW mice during acute disease rapidly decreased proteinuria, and the treated mice remained aproteinuric for at least 10 weeks. Control and CRP‐treated mice developed similar levels of anti‐dsDNA. In C57BL/6 mice, injection of CRP either before or after induction of NTN suppressed proteinuria and glomerular pathology. CRP was completely ineffective in treating NTN in interleukin‐10 (IL‐10)–deficient mice.CRP injection suppresses inflammation in the kidney in SLE and NTN. The requirement for IL‐10 in this protection suggests that CRP must rapidly initiate an IL‐10–dependent antiinflammatory process. These findings suggest that a major function of CRP during the acute‐phase response is to limit tissue damage and modulate acute inflammation. [ABSTRACT FROM AUTHOR]

Severe injury remains a leading cause of death and morbidity in patients under 40, with the number of annual trauma-related deaths approaching 160,000 in the United States. Patients who survive the initial trauma and post-traumatic resuscitation are at risk for immune dysregulation, which contributes to late mortality and accounts for approximately 20% of deaths after traumatic injury. This post-traumatic immunosuppressed state has been attributed to over-expression of anti-inflammatory mediators in an effort to restore host homeostasis. We measured a panel of monocyte markers and cytokines in 50 severely injured trauma patients for 3 days following admission. We made the novel observation that the subpopulation of monocytes expressing high levels of CD14 and CD16 was expanded in the majority of patients. These cells also expressed CD163 consistent with differentiation into alternatively activated macrophages with potential regulatory or wound-healing activity. We examined factors in trauma plasma that may contribute to the generation and activation of these cells. The percentage of CD14(high)CD16(+) monocytes after trauma correlated strongly with plasma C-reactive protein (CRP) transforming growth factor-β (TGF-β), and macrophage colony-stimulating factor (M-CSF) levels. We demonstrate a role for TGF-β and M-CSF, but not CRP in generating these cells using monocytes from healthy volunteers incubated with plasma from trauma patients. CD16 is a receptor for CRP and IgG, and we showed that monocytes differentiated to the CD14(high)CD16(+) phenotype produced anti-inflammatory cytokines in response to acute phase concentrations of CRP. The role of these cells in immunosuppression following trauma is an area of ongoing investigation.