EVIDENCE OF AUTOCRINE MODULATION OF MACROPHAGE NITRIC-OXIDE SYNTHASE BY ALPHA-MELANOCYTE-STIMULATING HORMONE

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a potent inhibitor y agent in all major forms of inflammation. To identify a potential me chanism of antiinflammatory action of alpha-MSH, we tested its effects on production of nitric oxide (NO), believed to be a mediator common to all forms of inflammation. We measured NO and alpha-MSH production in RAW 264.7 cultured murine macrophages stimulated with bacterial lip opolysaccharide and interferon gamma. alpha-MSH inhibited production o f NO, as estimated from nitrite production and nitration of endogenous macrophage proteins. This occurred through inhibition of production o f NO synthase II protein; steady-state NO synthase II mRNA abundance w as also reduced. alpha-MSH increased cAMP accumulation in RAW cells, c haracteristic of alpha-MSH receptors in other cell types. RAW cells al so expressed mRNA for the primary alpha-MSH receptor (melanocortin 1). mRNA for proopiomelanocortin, the precursor molecule of alpha-MSH, wa s expressed in RAW cells, and tumor necrosis factor ar increased produ ction and release of alpha-MSH. These results suggest that the proinfl ammatory cytokine tumor necrosis factor alpha can induce macrophages t o increase production of alpha-MSH, which then becomes available to ac t upon melanocortin receptors on the same cells. Such stimulation of m elanocortin receptors could modulate inflammation by inhibiting the pr oduction of NO. The results suggest that alpha-MSH is an autocrine fac tor in macrophages which modulates inflammation by counteracting the e ffects of proinflammatory cytokines.