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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 27; no. 5; pp. 1101 - 1107
• Main Authors: Zirlik, Andreas, Bavendiek, Udo, Libby, Peter, MacFarlane, Lindsey, Gerdes, Norbert, Jagielska, Joanna, Ernst, Sandra, Aikawa, Masanori, Nakano, Hiroyasu, Tsitsikov, Erdyni, Schönbeck, Uwe
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.05.2007; Hagerstown, MD Lippincott
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Blotting, Western; Cardiology. Vascular system; CD40 Ligand - immunology; Disease Progression; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug toxicity and drugs side effects treatment; Endothelial Cells - immunology; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelium, Vascular - immunology; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Fundamental and applied biological sciences. Psychology; Gene Expression; Humans; Inflammation - metabolism; Inflammation - pathology; Medical sciences; Mice; Pharmacology. Drug treatments; Polymerase Chain Reaction; RNA, Small Interfering - genetics; Saphenous Vein - drug effects; Saphenous Vein - metabolism; Saphenous Vein - pathology; TNF Receptor-Associated Factor 1 - genetics; TNF Receptor-Associated Factor 1 - metabolism; TNF Receptor-Associated Factor 2 - genetics; TNF Receptor-Associated Factor 2 - metabolism; TNF Receptor-Associated Factor 3 - genetics; TNF Receptor-Associated Factor 3 - metabolism; TNF Receptor-Associated Factor 5 - genetics; TNF Receptor-Associated Factor 5 - metabolism; TNF Receptor-Associated Factor 6 - genetics; TNF Receptor-Associated Factor 6 - metabolism; Toxicity: blood; Vertebrates: cardiovascular system; Vascular disease; CD40L; Endothelial cell; signaling; TRAF; Atherosclerotic plaque; Atherosclerosis; Cardiovascular disease; Inflammation
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.107.140566

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.