The role of nuclear factor-kappa B and melanogenesis in tumor necrosis factor-alpha-induced apoptosis of normal human melanocytes.
The proapoptotic potential of tumor necrosis factor-alpha (TNF-alpha) has been demonstrated for various cell types, whereas nuclear factor-kappaB (NF-kappaB) is known to support the transcription of prosurvival genes. In the present study, investigation of normal human melanocytes revealed induction of apoptosis after TNF-alpha treatment (100 U/ml) in only 3 out of 11 cultures analyzed, whereas 8 cultures remained largely resistant. In sensitive cultures, NF-kappaB binding activity was found increased after TNF-alpha treatment; apoptosis-resistant cells were characterized by relatively high basic NF-kappaB binding activities and did not show NF-kappaB activation after TNF-alpha treatment. Inhibition of NF-kappaB by a specific inhibitor, Bay-11, either induced apoptosis itself or resistant melanocyte cultures became sensitive to TNF-alpha treatment. No correlation was found between apoptosis sensitivity and the expression of TNF receptor-1 or the expression of Bax, Bcl-2 and Bcl-X(L). 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-kappaB activation. NF-kappaB mediates the transcription of antiapoptotic factors which may block TNF-alpha-induced apoptosis at early steps of the signal cascade.
Shang
Jing
J
Department of Dermatology, University Medical Center Benjamin Franklin, Free University of Berlin, Berlin, Germany.
Eberle
Jürgen
J
Geilen
Christoph C
CC
Hossini
Amir M
AM
Fecker
Lothar F
LF
Orfanos
Constantin E
CE
Tebbe
Beate
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012880:Skin Pigmentation / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha