{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:36:14Z","timestamp":1792701374049,"version":"4.5.0"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2016,12,8]],"date-time":"2016-12-08T00:00:00Z","timestamp":1481155200000},"content-version":"vor","delay-in-days":37,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA023074"],"award-info":[{"award-number":["CA023074"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 CA027502"],"award-info":[{"award-number":["P01 CA027502"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R03 CA167580"],"award-info":[{"award-number":["R03 CA167580"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007345","name":"University of Arizona Cancer Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007345","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Photochem &amp; Photobiology"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cutaneous exposure to solar ultraviolet (<jats:styled-content style=\"fixed-case\">UV<\/jats:styled-content>) radiation is a major causative factor in skin carcinogenesis, and improved molecular strategies for efficacious chemoprevention of nonmelanoma skin cancer (<jats:styled-content style=\"fixed-case\">NMSC<\/jats:styled-content>) are urgently needed. Toll\u2010like receptor 4 (<jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4) signaling has been shown to drive skin inflammation, photoimmunosuppression, and chemical carcinogenesis. Here we have examined the feasibility of genetic and pharmacological antagonism targeting cutaneous <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 for the suppression of <jats:styled-content style=\"fixed-case\">UV<\/jats:styled-content>\u2010induced <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010<jats:italic>\u03ba<\/jats:italic>B and <jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>\u20101 signaling in keratinocytes and mouse skin. Using immunohistochemical and proteomic microarray analysis of human skin, we demonstrate for the first time that a significant increase in expression of <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 occurs in keratinocytes during the progression from normal skin to actinic keratosis, also detectible during further progression to squamous cell carcinoma. Next, we demonstrate that siRNA\u2010based genetic <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 inhibition blocks <jats:styled-content style=\"fixed-case\">UV<\/jats:styled-content>\u2010induced stress signaling in cultured keratinocytes. Importantly, we observed that resatorvid (<jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>\u2010242), a molecularly targeted clinical <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 antagonist, blocks <jats:styled-content style=\"fixed-case\">UV<\/jats:styled-content>\u2010induced <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010<jats:italic>\u03ba<\/jats:italic>B and <jats:styled-content style=\"fixed-case\">MAP<\/jats:styled-content> kinase\/<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>\u20101 activity and cytokine expression (Il\u20106, Il\u20108, and Il\u201010) in cultured keratinocytes and in topically treated murine skin. Taken together, our data reveal that pharmacological <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 antagonism can suppress <jats:styled-content style=\"fixed-case\">UV<\/jats:styled-content>\u2010induced cutaneous signaling, and future experiments will explore the potential of <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4\u2010directed strategies for prevention of <jats:styled-content style=\"fixed-case\">NMSC<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/php.12659","type":"journal-article","created":{"date-parts":[[2016,11,10]],"date-time":"2016-11-10T14:37:02Z","timestamp":1478788622000},"page":"816-825","source":"Crossref","is-referenced-by-count":39,"title":["Resatorvid\u2010based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV\u2010induced NF\u2010<i>\u03ba<\/i>B and AP\u20101 Signaling in Keratinocytes and Mouse Skin"],"prefix":"10.1111","volume":"92","author":[{"given":"Jaroslav","family":"Janda","sequence":"first","affiliation":[{"name":"The University of Arizona Cancer Center Tucson AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nichole B.","family":"Burkett","sequence":"additional","affiliation":[{"name":"The University of Arizona Cancer Center Tucson AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Blohm\u2010Mangone","sequence":"additional","affiliation":[{"name":"The University of Arizona Cancer Center Tucson AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Huang","sequence":"additional","affiliation":[{"name":"The University of Arizona Cancer Center Tucson AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Curiel\u2010Lewandrowski","sequence":"additional","affiliation":[{"name":"The University of Arizona Cancer Center Tucson AZ"},{"name":"Department of Medicine The University of Arizona Tucson AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Alberts","sequence":"additional","affiliation":[{"name":"The University of Arizona Cancer Center Tucson AZ"},{"name":"Department of Medicine The University of Arizona Tucson AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Emanuel F.","family":"Petricoin","sequence":"additional","affiliation":[{"name":"Center for Applied Proteomics and Molecular Medicine George Mason University Manassas VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie S.","family":"Calvert","sequence":"additional","affiliation":[{"name":"Center for Applied Proteomics and Molecular Medicine George Mason University Manassas VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Einspahr","sequence":"additional","affiliation":[{"name":"The University of Arizona Cancer Center Tucson 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