Examinando por Autor "Loyola, Alejandra"

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    The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs
    (Academic Press, 2016-12) 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
    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/).
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    Ítem
    Wnt signaling induces transcription, spatial proximity, and translocation of fusion gene partners in human hematopoietic cells
    (American Society of Hematology, 2015-10) Ugarte, Giorgia D.; Vargas, Macarena F.; Medina, Matías A.; León, Pablo; Necuñir, David; Elorza, Alvaro A.; Gutiérrez, Soraya E.; Moon, Randall T.; Loyola, Alejandra; De Ferrari, Giancarlo V.
    Chromosomal translocations are frequently associated with a wide variety of cancers, particularly hematologic malignancies. A recurrent chromosomal abnormality in acute myeloid leukemia is the reciprocal translocation t(8;21) that fuses RUNX1 and ETO genes. We report here that Wnt/β-catenin signaling increases the expression of ETO and RUNX1 genes in human hematopoietic progenitors. We found that β-catenin is rapidly recruited into RNA polymerase II transcription factories (RNAPII-Ser5) and that ETO and RUNX1 genes are brought into close spatial proximity upon Wnt3a induction. Notably, long-term treatment of cells with Wnt3a induces the generation a frequent RUNX1-ETO translocation event. Thus, Wnt/β-catenin signaling induces transcription and translocation of RUNX1 and ETO fusion gene partners, opening a novel window to understand the onset/development of leukemia. © 2015 by The American Society of Hematology.