TRAF-1, -2, -3, -5, and -6 are induced in atherosclerotic plaques and differentially mediate proinflammatory functions of CD40L in endothelial cells.
Abstract | OBJECTIVE: 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.
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Authors | Andreas Zirlik, Udo Bavendiek, Peter Libby, Lindsey MacFarlane, Norbert Gerdes, Joanna Jagielska, Sandra Ernst, Masanori Aikawa, Hiroyasu Nakano, Erdyni Tsitsikov, Uwe Schönbeck |
Journal | Arteriosclerosis, thrombosis, and vascular biology
(Arterioscler Thromb Vasc Biol)
Vol. 27
Issue 5
Pg. 1101-7
(May 2007)
ISSN: 1524-4636 [Electronic] United States |
PMID | 17332487
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- RNA, Small Interfering
- TNF Receptor-Associated Factor 1
- TNF Receptor-Associated Factor 2
- TNF Receptor-Associated Factor 3
- TNF Receptor-Associated Factor 5
- TNF Receptor-Associated Factor 6
- CD40 Ligand
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Topics |
- Animals
- Atherosclerosis
(etiology, metabolism, pathology)
- Blotting, Western
- CD40 Ligand
(immunology)
- Disease Progression
- Endothelial Cells
(immunology, metabolism, pathology)
- Endothelium, Vascular
(immunology, metabolism, pathology)
- Gene Expression
- Humans
- Inflammation
(metabolism, pathology)
- Mice
- Polymerase Chain Reaction
- RNA, Small Interfering
(genetics)
- Saphenous Vein
(drug effects, metabolism, pathology)
- TNF Receptor-Associated Factor 1
(genetics, metabolism)
- TNF Receptor-Associated Factor 2
(genetics, metabolism)
- TNF Receptor-Associated Factor 3
(genetics, metabolism)
- TNF Receptor-Associated Factor 5
(genetics, metabolism)
- TNF Receptor-Associated Factor 6
(genetics, metabolism)
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