COMPLEMENT-INDUCED EXPRESSION OF CHEMOKINE GENES IN ENDOTHELIUM - REGULATION BY IL-1-DEPENDENT AND IL-1-INDEPENDENT MECHANISMS

Activation of complement in tale vicinity of endothelium is thought to contribute to the tissue manifestations of inflammatory and immune re sponses. Endothelial cells contribute to these processes in part by th e elaboration of chemokines that activate various leukocytes and direc t their migration into tissues, We investigated the mechanisms by whic h activation of complement on endothelial cell surfaces might influenc e the expression of chemokine genes in endothelial cells. In a model f or the immune reaction occurring in a xenograft, human serum, as a sou rce of xenoreactive anti-endothelial Abs and complement, induced expre ssion of the monocyte chemotactic protein-1 (MCP-1), IL-8, and RANTES genes. The MCP-1 and IL-8 genes were expressed within 3 h as a first p hase and at >12 h as a second phase. The RANTES gene was expressed in porcine endothelial cells only 12 h after exposure to human serum. The expression of these genes required activation of complement and assem bly of membrane attack complex, as it was inhibited by soluble CR1 and did mot occur in the absence of C8, The early phase of MCP-1 and IL-8 gene expression did not require de nova protein synthesis, The late p hase of MCP-1, IL-S, and RANTES gene expression predominantly required the production of IL-1 alpha as an intermediate step. The results ind icate that the expression of chemokine genes in endothelial cells occu rs as a function of differential responses to complement and may in pa rt be conditioned by the availability of IL-1 alpha.