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

Abstract

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.

• 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)

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

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)