Differential regulation of endothelial cell activation by complement and interleukin 1α

Activation of complement on endothelium triggers physiological changes that promote coagulation, thrombosis, and inflammation. Unlike agonists such as cytokines and endotoxin that induce these changes through transcription of many genes, complement, particularly the membrane attack complex, primarily induces release of IL-1 alpha by the endothelial cells; the cytokine may then be removed by normal blood flow or may promote activation of the full range of endothelial cell responses in an autocrine or paracrine manner. We studied the intracellular signaling pathways used by complement to activate interleukin (IL)-1 alpha transcription in cultured endothelial cells. The membrane attack complex and other pore-forming proteins stimulated calcineurin and activated selective transcription of the IL-1 alpha gene. In contrast, the action of cytokines such as IL-1 alpha was not selective and not dependent on calcineurin activity. Transcription of IL-1 alpha, whether stimulated by complement and calcineurin or by "conventional agonists," such as IL-1 alpha independent of calcineurin, proceeded via binding of nuclear factor kappa B transcriptional activators to the IL-1 alpha gene promoter. These findings define a molecular mechanism through which complement regulates IL-1 alpha production by endothelial cells and explain how blood flow may determine the extent of complement-stimulated inflammation.