title: IL-17F regulates psoriasis-associated genes through IκBζ.
abstract: Psoriasis is a common chronic inflammatory and immune-mediated skin disease. Antagonists of TNF-α and, recently, IL-17 have proven to be highly effective in the treatment for psoriasis; however, the molecular mechanisms involved in the pathogenesis of psoriasis are poorly understood. Recently, we presented evidence that IκBζ is a key regulator in the development of psoriasis through its role in mediating IL-17A-driven effects. Like IL-17A, IL-17F is produced by a variety of immune cells, and the expression of IL-17F is increased in psoriatic skin. The purpose of this study was to characterize the role of IL-17F in the regulation of IκBζ expression and to investigate whether IL-17F regulates psoriasis-associated genes in human keratinocytes through IκBζ. Here, we demonstrate that IL-17F stimulation induces IκBζ expression at both the mRNA and the protein levels in normal human keratinocytes. Moreover, silencing IκBζ by siRNA revealed that IκBζ is a key regulator of specific IL-17F-inducible psoriasis-associated genes and proteins, including DEFB4/hBD2, S100A7, CCL20, IL-8 and CHI3L1. In addition, IL-17F-induced IκBζ expression is mediated by a mechanism involving the p38 MAPK and NF-κB signalling pathways, as shown by the clear reduction in IL-17F-mediated expression of IκBζ during chemical inhibition of these two signalling pathways. In summary, we present IκBζ as a novel key regulator of IL-17F-driven effects in psoriasis. Thus, antagonists to IκBζ could potentially provide a more targeted approach for treating psoriasis as well as for treating the other inflammatory and immune-mediated diseases for which IL-17-targeting drugs have recently been approved.
authors: Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark.
authors: Trine
authors: T
authors: Bertelsen
authors: Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark.
authors: Christine
authors: C
authors: Ljungberg
authors: Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark.
authors: Rasmus
authors: R
authors: Boye Kjellerup
authors: Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark.
authors: Lars
authors: L
authors: Iversen
authors: Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark.
authors: Claus
authors: C
authors: Johansen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism; D000071451:Chitinase-3-Like Protein 1 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D020381:Interleukin-17 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D000075023:S100 Calcium Binding Protein A7 / Q000235:genetics / Q000276:immunology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D057134:Antibodies, Neutralizing; C108355:CCL20 protein, human; C084533:CHI3L1 protein, human; C508606:CXCL8 protein, human; D054418:Chemokine CCL20; D000071451:Chitinase-3-Like Protein 1; C106641:DEFB4A protein, human; D020672:I-kappa B Proteins; C508717:IL17A protein, human; C440021:IL17F protein, human; D020381:Interleukin-17; D016209:Interleukin-8; D016328:NF-kappa B; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000075023:S100 Calcium Binding Protein A7; C089242:S100A7 protein, human; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D048051:p38 Mitogen-Activated Protein Kinases
keywords: NF-κB; TNF-α; human keratinocytes; in vitro; interleukins