TRAF-1, -2, -3, -5, and -6 are induced in atherosclerotic plaques and differentially mediate proinflammatory functions of CD40L in endothelial cells.
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.


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.
Zirlik
Andreas
A
Donald W. Reynolds Cardiovascular Research Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Bavendiek
Udo
U
Libby
Peter
P
MacFarlane
Lindsey
L
Gerdes
Norbert
N
Jagielska
Joanna
J
Ernst
Sandra
S
Aikawa
Masanori
M
Nakano
Hiroyasu
H
Tsitsikov
Erdyni
E
Schönbeck
Uwe
U
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D023201:CD40 Ligand / Q000276:immunology*; D018450:Disease Progression; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D012501:Saphenous Vein / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics* / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics* / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics* / Q000378:metabolism; D048015:TNF Receptor-Associated Factor 5 / Q000235:genetics* / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics* / Q000378:metabolism
D034741:RNA, Small Interfering; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D023201:CD40 Ligand