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

Cristian Doñas, Macarena Carrasco, Macarena Fritz, Carolina Prado, Gabriela Tejón, Francisco Osorio-Barrios, Valeria Manríquez, Paz Reyes, Rodrigo Pacheco, María Rosa Bono, Alejandra Loyola, Mario Rosemblatt

Resultado de la investigación: Article

21 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)105-117
Número de páginas13
PublicaciónJournal of Autoimmunity
Volumen75
DOI
EstadoPublished - 1 dic 2016

Huella dactilar

Histone Demethylases
Dendritic Cells
Inflammation
Phenotype
Autoimmune Experimental Encephalomyelitis
Adoptive Transfer
Lysine
GSK-J4
Histones
Interleukin-6
Anti-Inflammatory Agents
Central Nervous System
Cytokines
T-Lymphocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Citar esto

Doñas, Cristian ; Carrasco, Macarena ; Fritz, Macarena ; Prado, Carolina ; Tejón, Gabriela ; Osorio-Barrios, Francisco ; Manríquez, Valeria ; Reyes, Paz ; Pacheco, Rodrigo ; Bono, María Rosa ; Loyola, Alejandra ; Rosemblatt, Mario. / The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs. En: Journal of Autoimmunity. 2016 ; Vol. 75. pp. 105-117.
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abstract = "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.",
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Doñas, C, Carrasco, M, Fritz, M, Prado, C, Tejón, G, Osorio-Barrios, F, Manríquez, V, Reyes, P, Pacheco, R, Bono, MR, Loyola, A & Rosemblatt, M 2016, 'The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs', Journal of Autoimmunity, vol. 75, pp. 105-117. https://doi.org/10.1016/j.jaut.2016.07.011

The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs. / Doñas, Cristian; Carrasco, Macarena; Fritz, Macarena; Prado, Carolina; Tejón, Gabriela; Osorio-Barrios, Francisco; Manríquez, Valeria; Reyes, Paz; Pacheco, Rodrigo; Bono, María Rosa; Loyola, Alejandra; Rosemblatt, Mario.

En: Journal of Autoimmunity, Vol. 75, 01.12.2016, p. 105-117.

Resultado de la investigación: Article

TY - JOUR

T1 - The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs

AU - Doñas, Cristian

AU - Carrasco, Macarena

AU - Fritz, Macarena

AU - Prado, Carolina

AU - Tejón, Gabriela

AU - Osorio-Barrios, Francisco

AU - Manríquez, Valeria

AU - Reyes, Paz

AU - Pacheco, Rodrigo

AU - Bono, María Rosa

AU - Loyola, Alejandra

AU - Rosemblatt, Mario

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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.

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KW - DCs

KW - GSK-J4

KW - H3K27me3

KW - JMJD3

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