title: UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription.
abstract: UVB irradiation potently induces cytokines in the skin, including IL-1alpha and tumor necrosis factor-alpha (TNF-alpha). The mechanism for TNF-alpha induction in UVB-irradiated keratinocytes is not clear. In this study, we explored the effects of UVB and cytokines, alone or in combination in human keratinocytes. Keratinocytes were sham- or UVB-irradiated with 30 mJ cm(-2), and then incubated in the absence or presence of IFN-alpha2b, TNF-alpha, or IL-1alpha. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts. Exogenous recombinant TNF-alpha up-regulates its own mRNA level. However, addition of IFN-alpha2b did not show any additive effect on TNF-alpha mRNA induction. To understand the regulation of TNF-alpha mRNA by UVB, with or without IL-1alpha, we examined the transcription rate and half-life of TNF-alpha mRNA. Treatment of keratinocytes with IL-1alpha or UVB alone increased TNF-alpha gene transcription 4- to 5-fold over sham treatment, and TNF-alpha gene transcription increased 11-fold in cells treated with UVB plus IL-1alpha over sham. UVB with IL-1alpha did not enhance the half-life of TNF-alpha mRNA over that seen with UVB alone. In conclusion, TNF-alpha expression in primary keratinocytes is upregulated transcriptionally by UVB and IL-1alpha.
authors.affiliation: Philadelphia V.A. Medical Center, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Bashir
authors.forename: Meena R
authors.initials: MR
authors.lastname: Sharma
authors.forename: Victoria P
authors.initials: VP
authors.lastname: Werth
mesh_terms: D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects*; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects / Q000528:radiation effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D014466:Ultraviolet Rays
chemical_list: D016898:Interferon-alpha; D053582:Interleukin-1alpha; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha