Nitric oxide modulates MCP-1 expression in endothelial cells: implications for the pathogenesis of pulmonary granulomatous vasculitis.
Monocyte chemoattractant protein-1 (MCP-1) is a pivotal mediator of angiocentric granuloma formation in glucan-induced pulmonary granulomatous vasculitis. Based on the rationale that mononuclear phagocytes retrieved from granulomas are rich sources of nitric oxide (NO) and that the recruitment of mononuclear phagocytes into lesions abates as granuloma formation slows, we tested the hypothesis that MCP-1 gene expression is regulated by a NO-sensitive mechanism. Preexposure of endothelial cell (EC) monolayers to NO donor compounds markedly reduced cytokine-induced MCP-1 expression and cytosolic-to-nuclear translocation of nuclear factor-kappa B (NF-kappaB), reversed fluctuations in endothelial reduced glutathione (GSH) pools but did not affect cGMP concentrations. The lungs of mice bearing targeted disruptions of the inducible nitric oxide synthase (iNOS) gene exhibited significantly higher concentrations of MCP-1 following glucan infusion than did those of wild-type mice. Cumulatively, these data suggest that NO suppresses MCP-1 expression by blunting the redox changes associated with cytokine-induced EC activation.
Desai
Anjali
A
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA.
Miller
Mark J
MJ
Huang
Xiaodong
X
Warren
Jeffrey S
JS
D000818:Animals; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D015769:Granuloma, Respiratory Tract / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D014657:Vasculitis / Q000378:metabolism*
D018932:Chemokine CCL2; D020030:Nitric Oxide Donors; D009569:Nitric Oxide