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Differential Regulation of Endothelial Cell Activation by Complement and Interleukin 1

From Transplantation Biology (G.J.B., S.S., J.L.P.) and the Departments of Pharmacology and Experimental Therapeutics (G.J.B.), Immunology (J.L.P.), Surgery (J.L.P.), and Pediatrics (J.L.P.), Mayo Clinic College of Medicine, Rochester, Minn.

Correspondence to Jeffrey L. Platt, MD, Transplantation Biology, Mayo Clinic, 200 First St SW, 2-66 Medical Sciences Building, Rochester, MN 55905. E-mail platt.jeffrey{at}mayo.edu

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 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 transcription in cultured endothelial cells. The membrane attack complex and other pore-forming proteins stimulated calcineurin and activated selective transcription of the IL-1 gene. In contrast, the action of cytokines such as IL-1 was not selective and not dependent on calcineurin activity. Transcription of IL-1, whether stimulated by complement and calcineurin or by "conventional agonists," such as IL-1 independent of calcineurin, proceeded via binding of nuclear factor B transcriptional activators to the IL-1 gene promoter. These findings define a molecular mechanism through which complement regulates IL-1 production by endothelial cells and explain how blood flow may determine the extent of complement-stimulated inflammation.

Key Words: calcineurin • complement • cyclosporine • endothelium • interleukin-1 • membrane attack complex • NF-B • FK506

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