The Role of Nuclear Factor-kappaB and Melanogenesis in Tumor Necrosis Factor-Alpha-Induced Apoptosis of Normal Human Melanocytes

Abstract

The proapoptotic potential of tumor necrosis factor-alpha (TNF-α) has been demonstrated for various cell types, whereas nuclear factor-kappaB (NF-ĸB) is known to support the transcription of prosurvival genes. In the present study, investigation of normal human melanocytes revealed induction of apoptosis after TNF-α treatment (100 U/ml) in only 3 out of 11 cultures analyzed, whereas 8 cultures remained largely resistant. In sensitive cultures, NF-ĸB binding activity was found increased after TNF-α treatment; apoptosis-resistant cells were characterized by relatively high basic NF-ĸB binding activities and did not show NF-ĸB activation after TNF-α treatment. Inhibition of NF-ĸB by a specific inhibitor, Bay-11, either induced apoptosis itself or resistant melanocyte cultures became sensitive to TNF-α treatment. No correlation was found between apoptosis sensitivity and the expression of TNF receptor-1 or the expression of Bax, Bcl-2 and Bcl-XL. A strong correlation, however, was found regarding the pigmentation degree, as high pigmentation correlated with apoptosis resistance and sensitive melanocyte cultures were weakly pigmented. These data may indicate that in cultured melanocytes, high levels of melanogenesis lead to an increase in oxidative stress which itself causes NF-ĸB activation. NF-ĸB mediates the transcription of antiapoptotic factors which may block TNF-α-induced apoptosis at early steps of the signal cascade.