C-Reactive Protein Stimulates MMP-1 Expression in U937 Histiocytes Through FcγRII and Extracellular Signal-Regulated Kinase Pathway:

Abstract

Objective-It has been shown that plasma level of C-reactive protein (CRP) is an independent predictor for acute coronary syndromes and is associated with plaque weakening. However, the underlying mechanisms are not well understood. In this study, we investigated the effect of CRP on the expression of matrix metalloproteinase-1 (MMP-1) that has been implicated in plaque vulnerability by human U937 histiocytes and monocyte-derived macrophages. Methods and Results-Enzyme-linked immunosorbent assay of MMP-1 in conditioned medium showed that treatment of U937 cells with 100 g/mL of CRP for 24 hour led to a 3-to 5-fold increase in MMP-1 secretion. CRP also markedly stimulated MMP-1 release from human monocyte-derived macrophages. In contrast, CRP had no effect on tissue inhibitor of metalloproteinase-1 (TIMP-1) secretion. Northern blot showed that CRP upregulated MMP-1 mRNA expression. Collagenase activity assay showed that CRP increased collagen-degrading activity in cell-conditioned medium. Furthermore, results showed that the stimulation of MMP-1 secretion by CRP was inhibited by anti-CD32, but not by anti-CD64 antibody, and by mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitor PD98059. Finally, Western blot showed that CRP stimulated phosphorylation of extracellular signal-regulated kinase. Key Words: C-reactive protein Ⅲ matrix metalloproteinase Ⅲ arteriosclerosis Ⅲ gene expression C -reactive protein (CRP) is one of acute phase proteins that react to inflammation rapidly. 1 CRP is mainly produced by hepatocytes and its expression is upregulated by inflammatory cytokines such as interleukin-6. 1 Previous studies have well documented that CRP plays a role in host defense against bacterial pathogens and clearance of apoptotic and necrotic cells. 2 However, recent studies have provided evidence that CRP also has undesirable effects, such as promotion of inflammatory process and inflammationassociated atherosclerosis. For example, several investigations have shown that CRP induces the expression of adhesion molecules and chemokines in human endothelial cells [3][4][5] and stimulates release of tissue factor from monocytes. 6 The pathological studies also revealed that CRP is present in atherosclerotic lesions but not in the normal vessel wall. 5,[7][8][9] Furthermore, more than two dozen clinical studies published in the past decade have demonstrated a correlation between plasma CRP levels and acute coronary syndromes. 10 -13 All these studies suggest that CRP may be involved in the progression of atherosclerosis. Conclusions-ThisPlaque rupture and erosion are believed to be the key events that trigger the formation of thrombus and subsequent acute coronary syndromes. 14,15 Because a large number of studies have shown the correlation between plasma CRP levels and acute coronary syndromes, 10 -13 the possible role of CRP in plaque vulnerability has been investigated. A recent histopathological study showed that serum CRP level in patients who died of severe coronary artery disease w...

C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser307 and Ser612 in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport

“…CRP is a member of the highly conserved pentraxin family and is produced mainly by hepatocytes in response to cytokines such as IL-6, IL-1, and TNF-α. CRP binds to the IgG receptors FC γ receptor (FcγR)I and FcγRII on the surface of cells [35,36] thus inducing their tyrosine phosphorylation, recruitment of spleen tyrosine kinase, and activation of Rho/Rho-kinase and MAPKs including MEK and ERK1/2, JNK, and p38MAPK [37]. The specific signalling pathway leading to upstream activation of JNK and MAPKs upon binding of CRP to FcγRI and FcγRII receptors is still undefined.…”

C-reactive protein stimulates superoxide anion release and tissue factor activity in vivo

“…Previously, CRP has been shown to mediate its biological effects in endothelial cells and monocyte-macrophages via CD32 and CD64 [3][4][5][10][11][12][24][25][26][27][28]. Thus, we examined the effects of antibodies to CD16, CD32 and CD64 on CRP-induced superoxide anion release and tissue factor activity.…”

Joint Effects of N-Terminal Pro-B-Type-Natriuretic Peptide and C-Reactive Protein vs Angiographic Severity in Predicting Major Adverse Cardiovascular Events and Clinical Restenosis After Coronary Angioplasty in Patients With Stable Coronary Artery Disease

“…2,23 Besides indicating an overall inflammatory state, plasma CRP might have a direct pathogenic effect by increasing plaque vulnerability and rupture, which further leads to acute ischemic complications. Increasing evidence has shown the role of CRP in atherothrombosis by inducing matrix metalloproteinases expression in endothelial cells and macrophages, 24 as well as promoting platelet activation and coagulation. 10,25 Thus, the rationale of combined determination of plasma CRP and NT-proBNP is to analyze the summation of actively inflamed and ischemic lesions, which might provide better risk stratification than the total burden of coronary atherosclerosis assessed by angiography.…”