title: The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
abstract: IL-19, IL-20, IL-22, IL-24, and IL-26 are members of the IL-10 family of cytokines that have been shown to be up-regulated in psoriatic skin. Contrary to IL-10, these cytokines signal using receptor complex R1 subunits that are preferentially expressed on cells of epithelial origin; thus, we henceforth refer to them as the IL-20 subfamily cytokines. In this study, we show that primary human keratinocytes (KCs) express receptors for these cytokines and that IL-19, IL-20, IL-22, and IL-24 induce acanthosis in reconstituted human epidermis (RHE) in a dose-dependent manner. These cytokines also induce expression of the psoriasis-associated protein S100A7 and keratin 16 in RHE and cause persistent activation of Stat3 with nuclear localization. IL-22 had the most pronounced effects on KC proliferation and on the differentiation of KCs in RHE, inducing a decrease in the granular cell layer (hypogranulosis). Furthermore, gene expression analysis performed on cultured RHE treated with these cytokines showed that IL-19, IL-20, IL-22, and IL-24 regulate many of these same genes to variable degrees, inducing a gene expression profile consistent with inflammatory responses, wound healing re-epithelialization, and altered differentiation. Many of these genes have also been found to be up-regulated in psoriatic skin, including several chemokines, beta-defensins, S100 family proteins, and kallikreins. These results confirm that IL-20 subfamily cytokines are important regulators of epidermal KC biology with potentially pivotal roles in the immunopathology of psoriasis.
authors.affiliation: Department of Pathology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Sa
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Valdez
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wu
authors.forename: Kenneth
authors.initials: K
authors.lastname: Jung
authors.forename: Fiona
authors.initials: F
authors.lastname: Zhong
authors.forename: Linda
authors.initials: L
authors.lastname: Hall
authors.forename: Ian
authors.initials: I
authors.lastname: Kasman
authors.forename: Jane
authors.initials: J
authors.lastname: Winer
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Dimitry M
authors.initials: DM
authors.lastname: Danilenko
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
mesh_terms: D000052:Acanthosis Nigricans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D004817:Epidermis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology*; D053536:Keratin-16 / Q000096:biosynthesis / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D011565:Psoriasis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; D007378:Interleukins; C507431:KRT16 protein, human; D053536:Keratin-16; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D016753:Interleukin-10; C422042:interleukin 20