title: Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes.
abstract: Bullous pemphigoid (BP) is the most common subepidermal autoimmune blistering skin disease characterized by autoantibodies against the hemidesmosomal proteins BP180 and BP230. The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses, and recent evidence suggests that it represents a novel treatment target in autoimmune bullous diseases. The aim of the study was to investigate the contribution of Hsp90 to the proinflammatory cytokine production in keratinocytes induced by autoantibodies to BP180 from BP patient serum. HaCaT cells were treated with purified human BP or normal IgG in the absence or presence of the Hsp90 blocker 17-DMAG and effects on viability, interleukin 6 (IL-6) and IL-8 (cytokines critical for BP pathology), NFκB (their major transcription factor), and Hsp70 (marker of effective Hsp90 inhibition and potent negative regulator of inflammatory responses) were investigated. We found that BP IgG stimulated IL-6 and IL-8 release from HaCaT cells and that non-toxic doses of 17-DMAG inhibited this IL-8, but not IL-6 secretion in a dose- and time-dependent fashion. Inhibition of this IL-8 production was also observed at the transcriptional level. In addition, 17-DMAG treatment blunted BP IgG-mediated upregulation of NFκB activity and was associated with Hsp70 induction. This study provides important insights that Hsp90 is involved as crucial regulator in anti-BP180 IgG-induced production of keratinocyte-derived IL-8. By adding to the knowledge of the multimodal anti-inflammatory effects of Hsp90 blockade, our data further support the introduction of Hsp90 inhibitors into the clinical setting for treatment of autoimmune diseases, especially for BP.
authors.affiliation: Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tukaj
authors.forename: Denise
authors.initials: D
authors.lastname: Grüner
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Michael
authors.initials: M
authors.lastname: Kasperkiewicz
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology; D016227:Benzoquinones / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D024041:Non-Fibrillar Collagens / Q000276:immunology; D010391:Pemphigoid, Bullous / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D000097805:Collagen Type XVII
chemical_list: D000893:Anti-Inflammatory Agents; D001323:Autoantibodies; D001324:Autoantigens; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII; C508606:CXCL8 protein, human; C508600:IL6 protein, human; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin