C-Reactive Protein Mediates Protection from Lipopolysaccharide Through Interactions With FcγR

Abstract

C-reactive protein (CRP) is a component of the acute phase response to infection, inflammation, and trauma. A major activity of acute phase proteins is to limit the inflammatory response. It has been demonstrated that CRP protects mice from lethal doses of LPS. In the mouse, CRP binds to the regulatory receptor, FcγRIIb, and to the γ-chain-associated receptor, FcγRI. The goal ofthis study was to determine whether FcγRs are necessary for the protective effect of CRP. The ability of CRP to protect mice from a lethal dose of LPS was confirmed using injections of 500 and 250 μg of CRP at 0 and 12 h. CRP treatment of FcγRIIb-deficient mice increased mortality after LPS challenge and increased serum levels of TNF and IL-12 in response to LPS. CRP did not protect FcR γ-chain-deficient mice from LPS-induced mortality. Treatment of normal mice, but not γ-chain-deficient mice, with CRP increased IL-10 levels following LPS injection. In vitro, in the presence of LPS, CRP enhanced IL-10 synthesis and inhibited IL-12 synthesis by bone marrow macrophages from normal, but not γ-chain-deficient mice. The protective effect of CRP appears to be mediated by binding to FcγRI and FcγRII resulting in enhanced secretion of the anti-inflammatory cytokine IL-10 and the down-regulation of IL-12. These results suggest that CRP can alter the cytokine profile of mouse macrophages by acting through FcγR leading to a down-regulation of the inflammatory response.

C‐reactive protein impairs human CD14+ monocyte‐derived dendritic cell differentiation, maturation and function

“…Therefore, CD32 could be one of the major CRP-binding receptors, and the engagement of CRP with CD32 could mediate major inhibition of DC differentiation. This observation is consistent with another study showing that CRP may act through FccR, thereby leading to down-regulation of the inflammatory response [10]. This data could also correlate well with our observations in Fig.…”

“…In vitro studies have shown that CRP displays both anti-inflammatory and pro-inflammatory effects [8,9]. CRP can enhance release of the antiinflammatory cytokine IL-10 and reduce IFN-c production [10]. CRP may inhibit antibody (Ab) responses to antigens by epitope blocking, a possible mechanism for inhibition of the immune responses to self-antigens [11].…”

Interleukin-1 Receptor Signaling Mediates Atherosclerosis Associated With Bacterial Exposure and/or a High-Fat Diet in a Murine Apolipoprotein E Heterozygote Model

“…Studies show that CRP, the human counterpart of SAA, can have a protective role in limiting the inflammatory response. 47,48 However, substantial data suggest that CRP exhibits direct proinflammatory effects on endothelial cells. 27 Elevated serum CRP is being taken as a powerful predictive marker of adverse outcome in ASVCD.…”

Human C-Reactive Protein Does Not Protect against Acute Lipopolysaccharide Challenge in Mice

“…There is also evidence that CRP may contribute to resistance against the lethal toxicity of Gram-negative bacterial LPS. This was first reported in transgenic mice expressing the rabbit CRP gene (21), and subsequently shown for wild-type mice to which human CRP was administered by injection (22,23). If such protection occurred in a The costs of publication of this article were defrayed in part by the payment of page charges.…”

“…injections of 5 or 10 mg/kg of LPS from E. coli O111:B4 (Sigma-Aldrich, St. Louis, MO) in solution in PBS. In additional experiments, LPS preparations (10 mg/kg) from E. coli O55:B5 and from S. typhimurium (both from Sigma-Aldrich) were used to replicate exactly the challenges reported in previously published studies (21)(22)(23). Lethality was monitored at 24-h intervals over 72 h. In some experiments, acute-phase responses in wild-type and human CRP transgenic mice were initiated 24 h before LPS challenge by s.c. injection of either 0.5 ml 10% (w/v) casein solution (ICN Pharmaceuticals, Costa Mesa, CA) in 0.05 M NaHCO 3 buffer (25) or 0.25 or 0.5 ml 2% w/v aqueous silver nitrate solution (Sigma-Aldrich) (26).…”