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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2533.)
© 2000 American Heart Association, Inc.

Vascular Biology

Fc- Receptor Cross-Linking by Immune Complexes Induces Matrix Metalloproteinase-1 in U937 Cells via Mitogen-Activated Protein Kinase

Yan Huang; Andrew J. Fleming; Shan Wu; Gabriel Virella; Maria F. Lopes-Virella

From the Division of Endocrinology, Diabetes, and Medical Genetics (Y.H., A.J.F., S.W., M.F.L.-V.), Department of Medicine, and the Department of Immunology and Microbiology (G.V.), Medical University of South Carolina, and the Ralph H. Johnson Veterans Administration Medical Center (Y.H., M.F.L.-V.), Charleston, SC.

Correspondence to Yan Huang, MD, PhD, Division of Endocrinology, Diabetes, and Medical Genetics, Department of Medicine, Medical University of South Carolina, 114 Doughty St, Charleston, SC 29403. E-mail huangyan{at}musc.edu

Abstract—Matrix metalloproteinase-1 (MMP-1) secreted by macrophages potentially contributes to plaque rupture. Because large quantities of immunoglobulin G and ICs (ICs), including low density lipoprotein–containing ICs (LDL-ICs), are present in atherosclerotic lesions, we examined the effect of LDL-ICs on macrophage MMP-1 expression. With the use of ICs prepared with human LDL and rabbit anti-LDL antiserum, our enzyme-linked immunosorbent assays and Northern blots showed that MMP-1 secretion and expression by U937 histiocytes were induced by LDL-ICs. Furthermore, our results showed that blocking of Fc- receptor I and II (FcRI and FcRII) inhibited 70% and 55%, respectively, of the LDL-IC–induced secretion of MMP-1. Finally, our data showed that both PD98059, an inhibitor of the mitogen-activated protein kinase pathway, and Ro-31-2880, an inhibitor of protein kinase C, inhibited LDL-IC–stimulated MMP-1 secretion in a dose-dependent manner, with 96% and 95% inhibition, respectively, at the respective doses of 50 µmol/L and 80 nmol/L. In conclusion, this study demonstrated for the first time that LDL-ICs induce macrophage MMP-1 secretion by cocross-linking FcRI and FcRII and triggering a protein kinase C–dependent mitogen-activated protein kinase pathway. These results suggest that LDL-ICs and other ICs localized in atherosclerotic plaques may be potent stimulators for macrophage MMP-1 expression and may contribute to plaque rupture and acute coronary events.

Key Words: LDL • metalloproteinase • immune complex • collagen

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