The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs

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dc.contributor.authorDoñas, Cristian
dc.contributor.authorCarrasco, Macarena
dc.contributor.authorFritz, Macarena
dc.contributor.authorPrado, Carolina
dc.contributor.authorTejón, Gabriela
dc.contributor.authorOsorio-Barrios, Francisco
dc.contributor.authorManríquez, Valeria
dc.contributor.authorReyes, Paz
dc.contributor.authorPacheco, Rodrigo
dc.contributor.authorBono, María Rosa
dc.contributor.authorLoyola, Alejandra
dc.contributor.authorRosemblatt, Mario
dc.date.accessioned2023-08-23T20:59:00Z
dc.date.available2023-08-23T20:59:00Z
dc.date.issued2016-12
dc.descriptionIndexación: Scopus.es
dc.description.abstractAs it has been established that demethylation of lysine 27 of histone H3 by the lysine-specific deme thylase JMJD3 increases immune responses and thus elicits inflammation, we hypothesize that inhibition of JMJD3 may attenuate autoimmune disorders. We found that in vivo administration of GSK-J4, a selective inhibitor of JMJD3 and UTX, ameliorates the severity of experimental autoimmune encephalomyelitis (EAE). In vitro experiments revealed that the anti-inflammatory effect of GSK-J4 was exerted through an effect on dendritic cells (DCs), promoting a tolerogenic profile characterized by reduced expression of costimulatory molecules CD80/CD86, an increased expression of tolerogenic molecules CD103 and TGF-b1, and reduced secretion of proin flammatory cytokines IL-6, IFN-g, and TNF. Adoptive transfer of GSK-J4-treated DCs into EAE mice reduced the clinical manifestation of the disease and decreased the extent of inflammatory CD4þ T cells infiltrating the central nervous system. Notably, Treg generation, stability, and suppressive activity were all exacerbated by GSK-J4-treated DCs without affecting Th1 and Th17 cell production. Our data show that GSK-J4-mediated modulation of inflammation is achieved by a direct effect on DCs and that systemic treatment with GSK-J4 or adoptive transfer of GSK-J4-treated DCs ex vivo may be promising approaches for the treatment of inflammatory and autoimmune disorders. © 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).es
dc.description.urihttps://www-sciencedirect-com.recursosbiblioteca.unab.cl/science/article/pii/S0896841116301196?via%3Dihub
dc.identifier.citationJournal of Autoimmunity. Volume 75, Pages 105 - 117. 1 December 2016es
dc.identifier.doi10.1016/j.jaut.2016.07.011
dc.identifier.issn0896-8411
dc.identifier.urihttps://repositorio.unab.cl/xmlui/handle/ria/52768
dc.language.isoenes
dc.publisherAcademic Presses
dc.rights.licenseAtribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/deed.es
dc.subjectGSK-J4es
dc.subjectAutoimmunityes
dc.subjectDCses
dc.subjectTreges
dc.subjectJMJD3es
dc.subjectH3K27me3es
dc.titleThe histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCses
dc.typeArtículoes
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