Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation

Atherosclerosis is an inflammatory disease of large arteries that is initia ted through the activation of endothelium by proinflammatory mediators. CD4 0 receptor stimulation has been implicated in the pathogenesis of atheroscl erosis. One of the most important atheroprotective stimuli is the viscous d rag (shear stress) generated by the streaming blood acting on the endotheli al monolayer. Here, we demonstrate that shear stress prevents CD40 ligand-i nduced endothelial cell activation, and we identify upregulation of TNF rec eptor-associated factor-3 (TRAF-3) as a potent CD40-inhibitory mechanism. S hear stress specifically upregulates TRAF-3 in cultured endothelial cells. Moreover, in the endothelial cells overlying human atherosclerotic plaques, TRAF-3 expression is upregulated in areas with high shear stress. Overexpr ession of TRAF-3 inhibits endothelial expression of proinflammatory cytokin es and tissue factor and blocks DNA-binding activity of the transcription f actor AP-1; it thereby prevents CD40-induced endothelial activation. Thus, upregulation of TRAF-3 represents a novel mechanism for preserving the func tional integrity of the endothelial monolayer.