The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs
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Fecha
2016-12
Profesor/a Guía
Facultad/escuela
Idioma
en
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Academic Press
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Licencia CC
Atribution 4.0 International (CC BY 4.0)
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https://creativecommons.org/licenses/by/4.0/deed.es
Resumen
As 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/).
Notas
Indexación: Scopus.
Palabras clave
GSK-J4, Autoimmunity, DCs, Treg, JMJD3, H3K27me3
Citación
Journal of Autoimmunity. Volume 75, Pages 105 - 117. 1 December 2016
DOI
10.1016/j.jaut.2016.07.011