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(Circulation Research. 2008;102:823.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Constitutive Repression of Interleukin-1 in Endothelial Cells

Gregory J. Brunn, Soheyla Saadi, Jeffrey L. Platt

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

Correspondence to Jeffrey L. Platt, MD, Department of Surgery, University of Michigan, 109 Zina Pitcher Pl, Ann Arbor, MI 48109-2200. E-mail plattjl{at}umich.edu

Activation of complement stimulates inflammation and provides an initial vigorous defense against infection. Insertion of the membrane attack complex in cell membranes of vascular endothelial cells induces changes in cell differentiation that promote coagulation, thrombosis, inflammation, and immunity. These changes are mediated by production of interleukin (IL)-1 by endothelial cells, which acts locally on endothelial cells to contain infection and promote healing of the affected site. In healthy tissues, however, promoting coagulation and inflammation would be dysphysiologic. Accordingly, endothelial cell activation by the membrane attack complex depends on both transcriptional regulation of IL-1 and availability of that cytokine to broadly modify endothelial cell physiology. Here, we report that the IL-1 gene contains a suppressor sequence that cooperates with histone modification to regulate production of IL-1 by endothelial cells. The suppressor sequence binds C/EBP (CCAAT enhancer–binding protein) family DNA-binding proteins isolated from the nucleus of quiescent endothelial cells. These results suggest constitutive suppression of IL-1 maintains quiescence of endothelium and that terminal complement complexes remove that suppression, allowing IL-1 transcription and, ultimately, activation of endothelium to proceed.

Key Words: calcineurin • complement • endothelium • histone deacetylase • inflammation • interleukin-1