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 melanin pigments which play a crucial protective role against skin photocarcinogenesis. In vivo, solar ultraviolet light triggers the secretion of numerous keratinocyte-derived factors that are implicated in the regulation of melanogenesis. Among these, tumor necrosis factor alpha (TNFalpha), a cytokine implicated in the pro-inflammatory response, down-regulates pigment synthesis in vitro. In this report, we aimed to determine the molecular mechanisms by which this cytokine inhibits melanogenesis in B16 melanoma cells. First, we show that TNFalpha inhibits the activity and protein expression of tyrosinase which is the key enzyme of melanogenesis. Further, we demonstrate that this effect is subsequent to a down-regulation of the tyrosinase promoter activity in both basal and cAMP-induced melanogenesis. Finally, we present evidence indicating that the inhibitory effect of TNFalpha on melanogenesis is dependent on nuclear factor kappa B (NFkappaB) activation. Indeed, overexpression of this transcription factor in B16 cells is sufficient to inhibit tyrosinase promoter activity. Furthermore, a mutant of inhibitory kappa B (IkappaB), that prevents NFkappaB activation, is able to revert the effect of TNFalpha on the tyrosinase promoter activity. Taken together, our results clarify the mechanisms by which TNFalpha inhibits pigmentation and point out the key role of NFkappaB in the regulation of melanogenesis.
Englaro
W
W
Institut National de la Sant'e et de la Recherche Médicale, U-385, Faculté de médecine, Nice. France.
Bahadoran
P
P
Bertolotto
C
C
Buscà
R
R
Dérijard
B
B
Livolsi
A
A
Peyron
J F
JF
Ortonne
J P
JP
Ballotti
R
R
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D003864:Depression, Chemical; D004790:Enzyme Induction / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D020672:I-kappa B Proteins; D008543:Melanins / Q000096:biosynthesis* / Q000235:genetics; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology; D011401:Promoter Regions, Genetic; D018808:Transcription Factor AP-1 / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008543:Melanins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase