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...