Transcriptional regulation of tumor necrosis factor-alpha in keratinocytes mediated by interleukin-1beta and tumor necrosis factor-alpha.
Irritant contact dermatitis (ICD) is an inflammatory skin reaction in which cytokines are thought to play a crucial role. In particular, tumor necrosis factor-alpha (TNF-alpha) has been implicated in the mechanism of this reaction. We report that interleukin-1beta (IL-1beta) that has been reported up-regulated in many inflammatory skin conditions is capable of increasing TNF-alpha mRNA and protein expression in murine keratinocytes. Furthermore, we show that TNF-alpha is capable of up-regulating itself in keratinocytes most likely in an autocrine manner. The signalling mechanisms involved in both IL-1beta- and TNF-alpha-mediated regulation of TNF-alpha are critically dependent upon protein kinase C (PKC), as demonstrated by blocking studies using protein kinase inhibitors. Furthermore, the increase in TNF-alpha mRNA expression seen after stimulation with rTNF-alpha and rIL-1beta involved increased transcription of TNF-alpha mRNA. This was demonstrated in a chloramphenicol acetyltransferase (CAT) assay using a CAT-construct containing the full-length TNF-alpha promoter. These observations support the notion of keratinocytes functioning as an amplifier of pro-inflammatory cytokine generation in the epidermis during ICD and other inflammatory skin conditions.
Lisby
S
S
Department of Dermatology, University of Copenhagen, Gentofte Hospital, Hellerup, Copenhagen, Denmark. Lisby@dadlnet.dk
Hauser
C
C
D000818:Animals; D007106:Immune Sera / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011493:Protein Kinase C / Q000502:physiology; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
C507764:Il1rn protein, mouse; D007106:Immune Sera; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C