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We found that a non\u2010cytotoxic concentration (MTT\u2010assay, CyQUANT\u2010assay) of fluoxetine significantly suppressed p(I:C)\u2010induced expression and release of several pro\u2010inflammatory cytokines (Q\u2010PCR, cytokine array, ELISA), and it decreased the release of the itch mediator endothelins (ELISA). These effects were not mediated by the inhibition of the NF\u2010\u03baB or p38 MAPK pathways (western blot), or by the suppression of the p(I:C)\u2010induced elevation of mitochondrial ROS production (MitoSOX Red labeling). Instead, unbiased activity profiling revealed that they were most likely mediated via the inhibition of the phosphoinositide 3\u2010kinase (PI3K) pathway. Importantly, the PI3K\u2010inhibitor GDC0941 fully mimicked the effects of fluoxetine (Q\u2010PCR, ELISA). Although fluoxetine was able to occupy the binding site of GDC0941 (in silico molecular docking), and exerted direct inhibitory effect on PI3K (cell\u2010free PI3K activity assay), it exhibited much lower potency and efficacy as compared to GDC0941. Finally, RNA\u2010Seq analysis revealed that fluoxetine deeply influenced the transcriptional alterations induced by p(I:C)\u2010treatment, and exerted an overall anti\u2010inflammatory activity. Collectively, our findings demonstrate that fluoxetine exerts potent anti\u2010inflammatory effects, and suppresses the release of the endogenous itch mediator endothelins in human keratinocytes, most likely via interfering with the PI3K pathway. Thus, clinical studies are encouraged to explore whether the currently reported beneficial effects translate in\u00a0vivo following its topical administration in inflammatory and pruritic dermatoses.<\/jats:p>","DOI":"10.1111\/exd.14988","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T01:44:59Z","timestamp":1703209499000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Fluoxetine exerts anti\u2010inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5184-8082","authenticated-orcid":false,"given":"Kinga Fanni","family":"T\u00f3th","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine University of Debrecen  Debrecen Hungary"},{"name":"University of Debrecen Doctoral School of Molecular Medicine  Debrecen Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3543-4146","authenticated-orcid":false,"given":"Dorottya","family":"\u00c1d\u00e1m","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine University of Debrecen  Debrecen Hungary"},{"name":"University of Debrecen Doctoral School of Molecular Medicine  Debrecen Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1976-1216","authenticated-orcid":false,"given":"J\u00f3zsef","family":"Arany","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine University of Debrecen  Debrecen Hungary"},{"name":"University of Debrecen Doctoral School of Molecular Medicine  Debrecen Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1399-8511","authenticated-orcid":false,"given":"Yesid A.","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Design and Applied Sciences, School of Applied Sciences and Sustainable Industry, Department of Pharmaceutical and Chemical Sciences, Faculty of Engineering Universidad Icesi  Cali Valle del Cauca Colombia"},{"name":"Cannaflos\u2014Gesellschaft f\u00fcr medizinisches Cannabis mbH  K\u00f6ln Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3770-6221","authenticated-orcid":false,"given":"Tam\u00e1s","family":"B\u00edr\u00f3","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine University of Debrecen  Debrecen Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2808-4475","authenticated-orcid":false,"given":"Jennifer I.","family":"Drake","sequence":"additional","affiliation":[{"name":"Eurofins Discovery  St. Charles Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0510-6931","authenticated-orcid":false,"given":"Alison","family":"O'Mahony","sequence":"additional","affiliation":[{"name":"Eurofins Discovery  St. Charles Missouri USA"},{"name":"Recursion  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6046-8236","authenticated-orcid":false,"given":"Attila G\u00e1bor","family":"Sz\u00f6ll\u0151si","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine University of Debrecen  Debrecen Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9722-251X","authenticated-orcid":false,"given":"Szil\u00e1rd","family":"P\u00f3liska","sequence":"additional","affiliation":[{"name":"Genomic Medicine and Bioinformatics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine University of Debrecen  Debrecen Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5011-8734","authenticated-orcid":false,"given":"Ana","family":"Kili\u0107","sequence":"additional","affiliation":[{"name":"Dr. August Wolff GmbH &amp; Co. 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