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The Effects of IL-20 Subfamily Cytokines on Reconstituted Human Epidermis Suggest Potential Roles in Cutaneous Innate Defense and Pathogenic Adaptive Immunity in Psoriasis

Susan M. Sa^*, Patricia A. Valdez, Jianfeng Wu, Kenneth Jung, Fiona Zhong^*, Linda Hall^*, Ian Kasman^*, Jane Winer, Zora Modrusan, Dimitry M. Danilenko^1,* and Wenjun Ouyang^1,

^* Department of Pathology, Department of Immunology, Department of Bioinformatics, and Department of Molecular Biology, Genentech, South San Francisco, CA 94080

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, -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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Wenjun Ouyang, Department of Immunology, Genentech, 1 DNA Way, MS 34, South San Francisco, CA 94080; E-mail address: ouyang{at}gene.com or Dr. Dimitry M. Danilenko, Genentech, 1 DNA Way, MS 72B, South San Francisco, CA 94080; E-mail address: danilenko.dimitry{at}gene.com

² Abbreviations used in this paper: KC, keratinocyte; CK16, cytokeratin 16; EGF, epidermal growth factor; EGFR, EGF receptor; HB, heparin binding; IHC, immunohistochemistry; KGF, KC growth factor; NHEK, normal human epidermal KC; pY, phosphotyrosine; RefSeq, reference sequence; RHE, reconstituted human epidermis; VEGF, vascular endothelial growth factor.

³ The online version of this article contains supplemental material.

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