title: IL-17A plays a central role in the expression of psoriasis signature genes through the induction of IκB-ζ in keratinocytes.
abstract: In psoriasis lesions, a diverse mixture of cytokines is up-regulated that influence each other generating a complex inflammatory situation. Although this is the case, the inhibition of IL-17A alone showed unprecedented clinical results in patients, indicating that IL-17A is a critical inducer of psoriasis pathogenesis. To elucidate IL-17A-driven keratinocyte-intrinsic signaling pathways, we treated monolayers of normal human epidermal keratinocytes in vitro with a mixture of six cytokines (IL-17A, TNF-α, IL-17C, IL-22, IL-36γ and IFN-γ) involved in psoriasis to mimic the inflammatory milieu in psoriasis lesions. Microarray and gene set enrichment analysis revealed that this cytokine mixture induced similar gene expression changes with the previous transcriptome studies using psoriasis lesions. Importantly, we identified a set of IL-17A-regulated genes in keratinocytes, which recapitulate typical psoriasis genes exemplified by DEFB4A, S100A7, IL19 and CSF3, based on the differences in the expression profiles of cells stimulated with six cytokines versus cells stimulated with only five cytokines lacking IL-17A. Furthermore, a specific IL-17A-induced gene, NFKBIZ, which encodes IκB-ζ, a transcriptional regulator for NF-κB, was demonstrated to have a significant role for IL-17A-induced gene expression. Thus, we present novel in vitro data from normal human keratinocytes that would help elucidating the IL-17A-driven keratinocyte activation in psoriasis.
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-Ku, Sapporo 060-0812, Japan muro@pharm.hokudai.ac.jp.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Muromoto
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-Ku, Sapporo 060-0812, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hirao
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-Ku, Sapporo 060-0812, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tawa
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-Ku, Sapporo 060-0812, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Hirashima
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-Ku, Sapporo 060-0812, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kon
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-Ku, Sapporo 060-0812, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kitai
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-Ku, Sapporo 060-0812, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002460:Cell Line; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D020672:I-kappa B Proteins / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology* / Q000473:pathology; D009687:Nuclear Proteins / Q000276:immunology*; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; C508717:IL17A protein, human; D020381:Interleukin-17; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins
keywords: cytokine; epidermal keratinocyte; inflammation; microarray; psoriasis