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

Arterioscler Thromb Vasc Biol. 2007 May;27(5):1101-7. doi: 10.1161/ATVBAHA.107.140566. Epub 2007 Mar 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / etiology*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Blotting, Western
  • CD40 Ligand / immunology*
  • Disease Progression
  • Endothelial Cells / immunology
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Gene Expression
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Mice
  • 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

Substances

  • 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