{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T20:27:42Z","timestamp":1780345662313,"version":"3.54.1"},"reference-count":53,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T00:00:00Z","timestamp":1684972800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pfizer","award":["58273087"],"award-info":[{"award-number":["58273087"]}]},{"name":"University of Rochester Department of Dermatology","award":["58273087"],"award-info":[{"award-number":["58273087"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Little is known about whether type 1 (IFN\u03b3), 2 (IL-4\/IL-13), or 3 (IL-17A\/IL-22) cytokines affect the susceptibility of keratinocytes (KC) to viruses. These immune pathways predominate in various skin diseases: lupus, atopic dermatitis (AD), and psoriasis, respectively. Janus kinase inhibitors (JAKi) are approved to treat both AD and psoriasis, and are in clinical development for lupus. We evaluated whether these cytokines alter viral susceptibility of KC and determined if this effect is modulated by treatment with JAKi. Viral susceptibility to vaccinia virus (VV) or herpes simplex virus-1 (HSV-1) \u00b1 JAKi was assessed in immortalized and primary human KC pretreated with cytokines. Exposure to type 2 (IL-4 + IL-13) or the type 3 (IL-22) cytokines significantly increased KC viral susceptibility. Specifically, there was a peak increase of 12.2 \u00b1 3.1-fold (IL-4 + IL-13) or 7.7 \u00b1 2.8-fold (IL-22) in VV infection as measured by plaque number. Conversely, IFN\u03b3 significantly reduced susceptibility to VV (63.1 \u00b1 64.4-fold). The IL-4 + IL-13-induced viral susceptibility was reduced (44 \u00b1 16%) by JAK1 inhibition, while the IL-22-enhanced viral susceptibility was diminished (76 \u00b1 19%) by TYK2 inhibition. IFN\u03b3-mediated resistance to viral infection was reversed by JAK2 inhibition (366 \u00b1 294% increase in infection). Cytokines expressed in AD skin (IL-4, IL-13, IL-22) increase KC viral susceptibility while IFN\u03b3 is protective. JAKi that target JAK1 or TYK2 reversed cytokine-enhanced viral susceptibility, while JAK2 inhibition reduced the protective effects of IFN\u03b3.<\/jats:p>","DOI":"10.3390\/ijms24119243","type":"journal-article","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T02:05:44Z","timestamp":1685066744000},"page":"9243","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["JAK Signaling Is Critically Important in Cytokine-Induced Viral Susceptibility of Keratinocytes"],"prefix":"10.3390","volume":"24","author":[{"given":"Kimberly A.","family":"Arnold","sequence":"first","affiliation":[{"name":"Departments of Dermatology, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3001-975X","authenticated-orcid":false,"given":"Liam F.","family":"Peterson","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8452-667X","authenticated-orcid":false,"given":"Lisa A.","family":"Beck","sequence":"additional","affiliation":[{"name":"Departments of Dermatology, University of Rochester Medical Center, Rochester, NY 14642, USA"},{"name":"Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7631-5234","authenticated-orcid":false,"given":"Matthew G.","family":"Brewer","sequence":"additional","affiliation":[{"name":"Departments of Dermatology, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.jaci.2014.11.001","article-title":"The 3 major types of innate and adaptive cell-mediated effector immunity","volume":"135","author":"Annunziato","year":"2015","journal-title":"J. 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