P315	The activated complement component C5a up-regulates the matrix metalloproteinases MMP-1 and MMP-9 in human monocyte derived macrophages.
1W.Speidl, 1S.P.Kastl, 1Chr.Kaun, 1Ph.J.Hohensinner, 1G.Maurer, 2K.Huber, 1J.Wojta
1Medical University of Vienna, Vienna, AT; 2Wilhelminenhospital, Vienna, AT.

Background. We have recently shown that serum levels of the complement component C5a predicts cardiovascular risk in patients with advanced atherosclerosis. Activation of complement may occur in atherosclerotic lesions. The anaphylotoxin C5a formed during activation of the complement cascade exerts chemotactic and proinflammatory effects. Macrophages may be involved in destabilization of atherosclerotic plaques by production of matrix metalloproteinases. We examined the effect of C5a on the production of matrix metalloproteinases (MMPs) and their inhibitors tissue inhibitors of MMPs (TIMPs) in human monocyte derived macrophages (MDM). Methods and Results. rhC5a increased MMP-1 and MMP-9 mRNA levels as detected by RealTime-PCR up to 6-fold, respectively. These results were confirmed on antigen level by ELISA. MMP-1 and MMP-9 activity also increased as detected by a specific activity assay. Levels of TIMP-1 and TIMP-2 mRNA and antigen was up-regulated up to 2-fold, respectively. Pertussis toxin or anti-C5a receptor antibodies, completely abolished the effect of rhC5a on MMP-1 production. Co-incubation with catalase showed no effect, suggesting that the C5a-induced up-regulation of MMP-1 and MMP-9 was not mediated by oxidative burst. Nuclear shift assay revealed that rhC5a stimulated activator protein-1 (AP-1) and NF-κB DNA binding. Conclusion: C5a induces the expression of MMP-1 and MMP-9 in human macrophages in vitro. If this effect is also present in vivo it may play a role in destabilization of atherosclerotic plaques.

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