title: Collagen XVII (BP180) modulates keratinocyte expression of the proinflammatory chemokine, IL-8.
abstract: Collagen XVII (COL17), a transmembrane protein expressed in epidermal keratinocytes (EK), is targeted by pathogenic autoantibodies in bullous pemphigoid. Treatment of EK with anti-COL17 autoantibodies triggers the production of proinflammatory cytokines. In this study, we test the hypothesis that COL17 is involved in the regulation of the EK proinflammatory response, using IL-8 expression as the primary readout. The absence of COL17 in EK derived from a junctional epidermolysis bullosa patient or shRNA-mediated knockdown of COL17 in normal EK resulted in a dysregulation of IL-8 responses under various conditions. The COL17-deficient cells showed an abnormally high IL-8 response after treatment with lipopolysaccharide (LPS), ultraviolet-B radiation or tumor necrosis factor, but exhibited a blunted IL-8 response to phorbol 12-myristate 13-acetate exposure. Induction of COL17 expression in COL17-negative EK led to a normalization of the LPS-induced proinflammatory response. Although α6β4 integrin was found to be up-regulated in COL17-deficient EK, siRNA-mediated knockdown of the α6 and β4 subunits revealed that COL17's effects on the LPS IL-8 response are not dependent on this integrin. In LPS-treated cells, inhibition of NF-kappa B activity in COL17-negative EK resulted in a normalization of their IL-8 response, and expression of an NF-kappa B-driven reporter was shown to be higher in COL17-deficient, compared with normal EK. These findings support the hypothesis that COL17 plays an important regulatory role in the EK proinflammatory response, acting largely via NF-kappa B. Future investigations will focus on further defining the molecular basis of this novel control network.
authors: Division of Rheumatology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Françoise
authors: F
authors: Van den Bergh
authors: Steven L
authors: SL
authors: Eliason
authors: Brian T
authors: BT
authors: Burmeister
authors: George J
authors: GJ
authors: Giudice
mesh_terms: D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004820:Epidermolysis Bullosa / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D039161:Integrin alpha6beta4 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D024041:Non-Fibrillar Collagens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014466:Ultraviolet Rays; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D039161:Integrin alpha6beta4; D020382:Interleukin-18; D008070:Lipopolysaccharides; D016328:NF-kappa B; D024041:Non-Fibrillar Collagens; D034741:RNA, Small Interfering; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha; D000097805:Collagen Type XVII