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.