COMPLEMENT-INDUCED RELEASE OF MONOCYTE CHEMOTACTIC PROTEIN-1 FROM HUMAN SMOOTH-MUSCLE CELLS - A POSSIBLE INITIATING EVENT IN ATHEROSCLEROTIC LESION FORMATION

Increasing evidence suggests that complement activation might represen t an important mechanism in early atherogenesis. Thus: complement comp onents, in particular the membrane attack complex (MAC) C5b-9(m), have been isolated from human atherosclerotic lesions. Furthermore, comple ment activation is known to occur in atherosclerotic lesions induced i n experimental animals, and the severity of cholesterol-induced plaque s is markedly reduced in complement-deficient animals. During atheroge nesis monocytes are recruited into the arterial wall, and a potent che moattractant for monocytes, monocyte chemotactic protein-1 (MCP-1), is expressed by vascular smooth muscle cells (SMCs). We hypothesized tha t generation of MACs on SMCs during the activation of complement might lead to the release of MCP-1 and hence to monocyte recruitment. In th is study, MACs were generated on human SMCs in vitro by sequential add ition of the purified complement components C5b6, C7, C8, and C9. The supernatant of the culture was chemotactic for freshly isolated periph eral blood monocytes in a modified Boyden chamber. The chemotactic act ivity of the supernatant was abolished by anti-MCP-1 blocking antibodi es but not by an isotype-matched antibody against an irrelevant antige n. The release of chemotactic activity was dependent on the dose of MA C formed on SMCs and was demonstrated within 10 minutes of exposure of the cells. The data support the hypothesis that complement-mediated r elease of MCP-1 from SMCs might be important in the recruitment of mon ocytes into the developing atherosclerotic lesion and could be an impo rtant initiating event in atherogenesis.