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

2007; Lippincott Williams & Wilkins; Volume: 27; Issue: 5 Linguagem: Inglês

10.1161/atvbaha.107.140566

1524-4636

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

Atherosclerosis and Cardiovascular Diseases

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.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.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.