Tumor necrosis factor alpha-mediated inhibition of melanogenesis is dependent on nuclear factor kappa B activation

Melanogenesis is a physiological process resulting in the synthesis of mela nin pigments which play a crucial protective role against skin photocarcino genesis. lit vivo, solar ultraviolet light triggers the secretion of numero us keratinocyte-derived factors that are implicated in the regulation of me lanogenesis. Among these, tumor necrosis factor alpha. (TNF alpha), a cytok ine implicated in the pro-inflammatory response, down-regulates pigment syn thesis in vitro. In this report, we aimed to determine the molecular mechan isms by which this cytokine inhibits melanogenesis in B16 melanoma cells. F irst, we show that TNF alpha inhibits the activity and protein expression o f tyrosinase which is the key enzyme of melanogenesis, Further, we demonstr ate that this effect is subsequent to a down-regulation of the tyrosinase p romoter activity in both basal and cAMP-induced melanogenesis, Finally, we present evidence indicating that the inhibitory effect of TNF alpha on mela nogenesis is dependent on nuclear factor kappa B (NF kappa B) activation. I ndeed, overexpression of this transcription factor in B16 cells is sufficie nt to inhibit tyrosinase promoter activity, Furthermore, a mutant of inhibi tory kappa B (I kappa B), that prevents NF kappa B activation, is able to r evert the effect of TNF alpha on the tyrosinase promoter activity. Taken to gether, our results clarify the mechanisms by which TNF alpha inhibits pigm entation and point out the key role of NF kappa B in the regulation of mela nogenesis.