on March 1, 2007
Published online before print March 1, 2007, doi: 10.1161/ATVBAHA.107.140566
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on February 6, 2006
Accepted on February 7, 2007
TRAF-1, -2, -3, -5, and -6 Are Induced in Atherosclerotic Plaques and Differentially Mediate Proinflammatory Functions of CD40L in Endothelial Cells
Andreas Zirlik ;
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, NY.
* To whom correspondence should be addressed. 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.
Key words: atherosclerosis • CD40L • inflammation • signaling • TRAF
This article has been cited by other articles:
 |
|
 |
|
  A. Dupoux, J. Cartier, S. Cathelin, R. Filomenko, E. Solary, and L. Dubrez-Daloz cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand Blood, January 1, 2009; 113(1): 175 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. P. C. Donners, L. Beckers, D. Lievens, I. Munnix, J. Heemskerk, B. J. Janssen, E. Wijnands, J. Cleutjens, A. Zernecke, C. Weber, et al. The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling Blood, May 1, 2008; 111(9): 4596 - 4604. [Abstract] [Full Text] [PDF]
|
|