Impaired PI3K/Akt activation-mediated NF-kappaB inactivation under elevated TNF-alpha is more vulnerable to apoptosis in vitiliginous keratinocytes.
Levels of the cytokines IL-6, IL-1alpha, and tumor necrosis factor-alpha (TNF-alpha) are significantly higher in lesional than in non-lesional skin of patients with vitiligo. However, how cytokines affect pigmentation is not fully understood. To examine the mechanism, Western blot analysis with TNF-alpha, Fas ligand (FasL), and downstream signaling molecules such as I-kappaB, NF-kappaB, TNF-R1-associated factor 2, Akt, and PTEN (phosphatase and tension homologue) were performed for the suction-blistered depigmented and normally pigmented epidermis from 10 patients. Levels of TNF-alpha and FasL were significantly higher in the depigmented epidermis. Interestingly, phosphorylation levels of I-kappaB, NF-kappaB, and Akt were lower in the depigmented epidermis. Moreover, PTEN, which could inhibit the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, was significantly higher in depigmented epidermis, implying that vitiliginous keratinocytes may be more susceptible to TNF-alpha-mediated apoptosis through impaired Akt and NF-kappaB activation. To test this hypothesis, cultured normal human keratinocytes were treated with TNF-alpha in the presence of a PI3K inhibitor to suppress Akt activation. Keratinocytes showing impaired Akt activation demonstrated increased apoptosis with less activation of NF-kappaB. Thus, reduced activation of NF-kappaB via impaired PI3K/Akt activation under increased TNF-alpha levels could result in increased apoptosis of vitiliginous keratinocytes.
Kim
Nan-Hyung
NH
Department of Dermatology, Dongguk University School of Medicine, Gyenggi-do, South Korea.
Jeon
Songhee
S
Lee
Hyun-Joo
HJ
Lee
Ai-Young
AY
D000293:Adolescent; D000328:Adult; D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D002648:Child; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D014820:Vitiligo / Q000378:metabolism* / Q000473:pathology; D000077191:Wortmannin
D000730:Androstadienes; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D000077191:Wortmannin