Monocyte chemoattractant protein-1 (MCP-1) plays an important role in glomerulonephritis and nitric oxide (NO) exerts a variety of renal pathophysiological effects. We investigated the effect of exogenous NO on pro-inflammatory cytokine-induced MCP-1 expression in human mesangial cells and its signal transduction pathway. Cells were pretreated with NO donors such as 3-morpholino-sydnonimine (SIN-1) or nitroprusside, and then stimulated with tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β). MCP-1 expression of mRNA and protein were measured by Northern blot analysis and ELISA. NF-ĸB binding activity was determined by electrophoretic mobility shift assay. Degradation of IĸB-α protein was assessed by Western blot analysis. SIN-1 inhibited TNF-α- or IL-1β-induced MCP-1 mRNA expression in a dose-dependent manner and also suppressed the MCP-1 protein expression. Nitroprusside inhibited the MCP-1 mRNA expression as well. SIN-1 dose dependently inhibited the TNF-α- or IL-1β-induced NF-ĸB binding activity and suppressed the TNF-α-induced degradation of IĸB-α. Analogue of cGMP (8-bromo-cGMP) had no significant effect on TNF-α-induced MCP-1 mRNA expression and guanylate cyclase inhibitor (ODQ) also had no significant influence on the inhibitory effect of SIN-1. These results suggest that exogenous NO inhibits MCP-1 expression via suppression of NF-ĸB by reducing the degradation of IĸB-α and through a cGMP-independent pathway.

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