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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1101.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

TRAF-1, -2, -3, -5, and -6 Are Induced in Atherosclerotic Plaques and Differentially Mediate Proinflammatory Functions of CD40L in Endothelial Cells

Andreas Zirlik; Udo Bavendiek; Peter Libby; Lindsey MacFarlane; Norbert Gerdes; Joanna Jagielska; Sandra Ernst; Masanori Aikawa; Hiroyasu Nakano; Erdyni Tsitsikov; Uwe Schönbeck

From Donald W. Reynolds Cardiovascular Research Center (A.Z., U.B., L.M., N.G., M.A., P.L., U.S.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; Department of Cardiology (A.Z., S.E.), University of Freiburg, Germany; Department of Cardiology (U.B., J.J.), Hannover Medical School, Hannover, Germany; Department of Immunology (H.N.), Juntendo University, School of Medicine, Tokyo, Japan; Department of Immunology (E.T.), Children’s Hospital, Harvard Medical School, Boston, Mass; Cardiovascular Disease (U.S.), Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Conn.

Correspondence to Peter Libby, MD, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, NRB-741, Boston, MA 02115. E-mail plibby{at}rics.bwh harvard.edu.

Objective— Several lines of evidence implicate CD40 ligand (CD40L, CD154) as a mediator and marker of atherosclerosis. This study investigated the involvement of tumor necrosis factor receptor-associated factors (TRAFs) in CD40 signaling in endothelial cells (ECs) and their expression in atheromata and cells involved in atherogenesis.

Methods and Results— CD40L enhanced the basal expression of TRAF-1, -2, -3, and 6, but not TRAF-5 in ECs. TRAFs associated with CD40 on ligation by CD40L. Study of ECs from TRAF-1, -2, and -5-deficient mice demonstrated functional involvement of TRAFs in proinflammatory CD40 signaling. Whereas TRAF-1 deficiency enhanced CD40L-induced IL-6 and MCP-1 expression, TRAF-2 and TRAF-5 deficiency inhibited CD40L-inducible IL-6 but not MCP-1 expression. Gene silencing in human ECs further delineated functions of TRAFs in CD40 signaling. TRAF-3 silencing in ECs showed increased CD40L-induced IL-6, MCP-1, and IL-8 expression, whereas TRAF-6 silencing increased selectively CD40L-induced MCP-1 expression. Enhanced TRAF levels in atherosclerotic lesions further supports involvement of members of this family of signaling molecules in arterial disease.

Conclusions— These results implicate endothelial TRAF-1, -2, -3, -5, and -6 in CD40 signaling in atherogenesis, identifying these molecules as potential targets for selective therapeutic intervention.

This study tested the hypothesis that TRAF-1, -2, -3, -5, and -6 participate in CD40 signaling in ECs. TRAFs differentially mediated CD40L-induced IL-6, IL-8, and MCP-1 expression and atherosclerotic arteries overexpressed TRAFs, identifying these signaling molecules as potential therapeutic targets.

Key Words: atherosclerosis • CD40L • inflammation • signaling • TRAF

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