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The highest constitutive IL\u201038 expression is detected in the skin, where it is mainly produced by differentiating keratinocytes. However, little data are available regarding its biological functions. In this study, we investigated the role of IL\u201038 in skin physiology. We demonstrate here that dermal fibroblasts and epithelial cells of skin appendages, such as eccrine sweat glands and sebaceous glands, also express IL\u201038. Next, using two\u2010 and three\u2010dimensional cell cultures, we show that endogenous expression of IL\u201038 correlates with keratinocyte differentiation and its ectopic overexpression inhibits keratinocyte proliferation and enhances differentiation. Accordingly, immunohistochemical analysis revealed downregulation of IL\u201038 in skin pathologies characterized by keratinocyte hyperproliferation, such as psoriasis and basal or squamous cell carcinoma. Finally, intracellular IL\u201038 can shuttle between the nucleus and the cytoplasm and its overexpression modulates the activity of the transcription regulators YAP and ID1. Our results indicate that IL\u201038 can act independently from immune system activation and suggest that it may affect the epidermis directly by decreasing proliferation and promoting differentiation of keratinocytes. These data suggest an important role of keratinocyte\u2010derived IL\u201038 in skin homeostasis and pathologies characterized by epidermal alterations.<\/jats:p>","DOI":"10.1111\/exd.14644","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T08:01:31Z","timestamp":1657785691000},"page":"1699-1711","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["<scp>IL<\/scp>\u201038 orchestrates proliferation and differentiation in human keratinocytes"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0308-8488","authenticated-orcid":false,"given":"Lo\u00efc","family":"Mermoud","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, Faculty of Medicine University of Geneva  Geneva Switzerland"},{"name":"Division of Rheumatology, Department of Medicine, Faculty of Medicine University of Geneva  Geneva 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