The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs
Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved..
As it has been established that demethylation of lysine 27 of histone H3 by the lysine-specific demethylase 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-β1, and reduced secretion of proinflammatory cytokines IL-6, IFN-γ, 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 CD4+ 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:75 |
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| Enthalten in: |
Journal of autoimmunity - 75(2016) vom: 01. Dez., Seite 105-117 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Doñas, Cristian [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.06.2017 Date Revised 10.04.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jaut.2016.07.011 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM263467325 |
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| 520 | |a Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a As it has been established that demethylation of lysine 27 of histone H3 by the lysine-specific demethylase 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-β1, and reduced secretion of proinflammatory cytokines IL-6, IFN-γ, 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 CD4+ 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Autoimmunity | |
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| 700 | 1 | |a Osorio-Barrios, Francisco |e verfasserin |4 aut | |
| 700 | 1 | |a Manríquez, Valeria |e verfasserin |4 aut | |
| 700 | 1 | |a Reyes, Paz |e verfasserin |4 aut | |
| 700 | 1 | |a Pacheco, Rodrigo |e verfasserin |4 aut | |
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| 700 | 1 | |a Loyola, Alejandra |e verfasserin |4 aut | |
| 700 | 1 | |a Rosemblatt, Mario |e verfasserin |4 aut | |
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