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GADD45 proteins mediate DNA repair in different cells including keratinocytes. In the immune system, GADD45a and GADD45b regulate the function and activation of both T lymphocytes and dendritic cells and GADD45a links DNA repair and epigenetic regulation through its demethylase activity. Here, we analyzed the expression of GADD45a and GADD45b in the skin, dendritic cells and circulating T cells in a cohort of psoriasis patients and their regulation by inflammatory signals. Thirty patients (17 male\/13 female) with plaque psoriasis and 15 controls subjects (7 male\/8 female), were enrolled. Psoriasis patients exhibited a lower expression of GADD45a at the epidermis but a higher expression in dermal infiltrating T cells in lesional skin. The expression of GADD45a and GADD45b was also higher in peripheral T cells from psoriasis patients, although no differences were observed in p38 activation. The expression and methylation state of the GADD45a target UCHL1 were evaluated, revealing a hypermethylation of its promoter in lesional skin compared to controls. Furthermore, reduced levels of GADD45a correlated with a lower expression UCHL1 in lesional skin. We propose that the demethylase function of GADD45a may account for its pleiotropic effects, and the complex and heterogeneous pattern of expression observed in psoriatic disease.<\/jats:p>","DOI":"10.1038\/s41598-021-93780-x","type":"journal-article","created":{"date-parts":[[2021,7,16]],"date-time":"2021-07-16T06:03:33Z","timestamp":1626415413000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Growth arrest and DNA damage-inducible proteins (GADD45) in psoriasis"],"prefix":"10.1038","volume":"11","author":[{"given":"Pedro","family":"Rodr\u00edguez-Jim\u00e9nez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lola","family":"Fern\u00e1ndez-Messina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda C.","family":"Ovejero-Benito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Chicharro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Vera-Tom\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Vara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danay","family":"Cibrian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Mart\u00ednez-Fleta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Jim\u00e9nez-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"S\u00e1nchez-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"Llamas-Velasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Abad-Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"S\u00e1nchez-Madrid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esteban","family":"Dauden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hortensia","family":"de la Fuente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,16]]},"reference":[{"key":"93780_CR1","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/978-1-4614-8289-5_4","volume":"793","author":"I Schmitz","year":"2013","unstructured":"Schmitz, I. Gadd45 proteins in immunity. Adv. Exp. Med. Biol. 793, 51\u201368. https:\/\/doi.org\/10.1007\/978-1-4614-8289-5_4 (2013).","journal-title":"Adv. Exp. Med. Biol."},{"key":"93780_CR2","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/s1074-7613(01)00141-8","volume":"14","author":"B Lu","year":"2001","unstructured":"Lu, B. et al. GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. Immunity 14, 583\u2013590. https:\/\/doi.org\/10.1016\/s1074-7613(01)00141-8 (2001).","journal-title":"Immunity"},{"key":"93780_CR3","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/ni1020","volume":"5","author":"B Lu","year":"2004","unstructured":"Lu, B., Ferrandino, A. F. & Flavell, R. A. Gadd45beta is important for perpetuating cognate and inflammatory signals in T cells. Nat. Immunol. 5, 38\u201344. https:\/\/doi.org\/10.1038\/ni1020 (2004).","journal-title":"Nat. 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Immunity 16, 499\u2013508. https:\/\/doi.org\/10.1016\/s1074-7613(02)00302-3 (2002).","journal-title":"Immunity"},{"key":"93780_CR6","doi-asserted-by":"publisher","first-page":"4153","DOI":"10.4049\/jimmunol.178.7.4153","volume":"178","author":"L Jirmanova","year":"2007","unstructured":"Jirmanova, L., Jankovic, D., Fornace, A. J. Jr. & Ashwell, J. D. Gadd45alpha regulates p38-dependent dendritic cell cytokine production and Th1 differentiation. J. Immunol. 178, 4153\u20134158. https:\/\/doi.org\/10.4049\/jimmunol.178.7.4153 (2007).","journal-title":"J. Immunol."},{"key":"93780_CR7","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1084\/jem.20051359","volume":"202","author":"L Liu","year":"2005","unstructured":"Liu, L. et al. Gadd45 beta and Gadd45 gamma are critical for regulating autoimmunity. J. Exp. Med. 202, 1341\u20131347. https:\/\/doi.org\/10.1084\/jem.20051359 (2005).","journal-title":"J. Exp. 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Endocrinology 159, 1172\u20131186. https:\/\/doi.org\/10.1210\/en.2017-00686 (2018).","journal-title":"Endocrinology"},{"key":"93780_CR14","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1164\/rccm.201103-0447OC","volume":"184","author":"S Mitra","year":"2011","unstructured":"Mitra, S. et al. Role of growth arrest and DNA damage-inducible alpha in Akt phosphorylation and ubiquitination after mechanical stress-induced vascular injury. Am. J. Respir. Crit. Care Med. 184, 1030\u20131040. https:\/\/doi.org\/10.1164\/rccm.201103-0447OC (2011).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"93780_CR15","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1007\/s00403-012-1246-0","volume":"304","author":"L Emtestam","year":"2012","unstructured":"Emtestam, L., Hagstromer, L., Dou, Y. C., Sartorius, K. & Johansson, O. PGP 9.5 distribution patterns in biopsies from early lesions of atopic dermatitis. Arch. Dermatol. 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MC Ovejero-Benito has potential conflicts of interest (honoraria for speaking and research support) with Janssen-Cilag and Leo Pharma, respectively. No other authors have potential conflicts of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"14579"}}