title: The autocrine TNFalpha signalling loop in keratinocytes requires atypical PKC species and NF-kappaB activation but is independent of cholesterol-enriched membrane microdomains.
abstract: Tumor necrosis factor alpha (TNFalpha) is involved in the pathogenesis of many inflammatory skin diseases. Epidermal keratinocytes produce and respond to TNFalpha via the cognate type 1 receptor (TNFR1). Little is known about regulation of TNFalpha signalling in this cell type. In this study, we report that in keratinocytes TNFalpha upregulates its own mRNA synthesis in an autocrine manner. This response peaks at approximately 1h of stimulation with TNFalpha but sustained elevated levels of TNFalpha mRNA are observed for up to 24h after stimulation and are dependent on the presence of the soluble cytokine. This autocrine response is mediated by the signalling cascade comprising TNFR1, atypical protein kinase C (aPKC) species and the transcription factor NF-kappaB, but is not dependent on the integrity of cholesterol-enriched membrane microdomains (lipid rafts). TNFalpha-stimulated keratinocytes produced the membrane-bound form of TNFalpha. It is conceivable that the described autocrine signalling loop contributes to the proinflammatory TNFalpha effect in the skin. The discovery of the crucial roles of aPKC and NF-kappaB might have consequences for the development of more selective anti-TNFalpha therapies for inflammatory skin diseases.
authors.affiliation: Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Lisby
authors.forename: Annesofie
authors.initials: A
authors.lastname: Faurschou
authors.forename: Robert
authors.initials: R
authors.lastname: Gniadecki
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D000069285:Infliximab; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D021962:Membrane Microdomains / Q000737:chemistry / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D045789:Sesquiterpenes, Guaiane; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D002227:Carbazoles; D007211:Indoles; D016328:NF-kappa B; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D014409:Tumor Necrosis Factor-alpha; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C081021:Go 6976; C001329:helenalin; D002784:Cholesterol; D000069285:Infliximab; D011493:Protein Kinase C