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

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.

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 ... -  《-》

The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation.

Interleukin (IL) 17-producing T helper (Th17) cells play critical roles in the clearance of extracellular bacteria and fungi as well as the pathogenesis of various autoimmune diseases, such as multiple sclerosis, psoriasis, and ulcerative colitis. Although a global transcriptional regulatory network of Th17 cell differentiation has been mapped recently, the participation of epigenetic modifications in the differentiation process has yet to be elucidated. We demonstrated here that histone H3 lysine-27 (H3K27) demethylation, predominantly mediated by the H3K27 demethylase Jmjd3, crucially regulated Th17 cell differentiation. Activation of naïve CD4(+) T cells immediately induced high expression of Jmjd3. Genetic depletion of Jmjd3 in CD4(+) T cells specifically impaired Th17 cell differentiation both in vitro and in vivo. Ectopic expression of Jmjd3 largely rescued the impaired differentiation of Th17 cells in vitro in Jmjd3-deficient CD4(+) T cells. Importantly, Jmjd3-deficient mice were resistant to the induction of experimental autoimmune encephalomyelitis (EAE). Furthermore, inhibition of the H3K27 demethylase activity with the specific inhibitor GSK-J4 dramatically suppressed Th17 cell differentiation in vitro. At the molecular level, Jmjd3 directly bound to and reduced the level of H3K27 trimethylation (me3) at the genomic sites of Rorc, which encodes the master Th17 transcription factor Rorγt, and Th17 cytokine genes such as Il17, Il17f, and Il22. Therefore, our studies established a critical role of Jmjd3-mediated H3K27 demethylation in Th17 cell differentiation and suggest that Jmjd3 can be a novel therapeutic target for suppressing autoimmune responses.

Liu Z ，Cao W ，Xu L ，Chen X ，Zhan Y ，Yang Q ，Liu S ，Chen P ，Jiang Y ，Sun X ，Tao Y ，Hu Y ，Li C ，Wang Q ，Wang Y ，Chen CD ，Shi Y ，Zhang X ... -  《-》

H3K27me3 demethylases regulate in vitro chondrogenesis and chondrocyte activity in osteoarthritis.

Yapp C ，Carr AJ ，Price A ，Oppermann U ，Snelling SJ ... -  《-》

Jumonji domain containing-3 (JMJD3) inhibition attenuates IL-1β-induced chondrocytes damage in vitro and protects osteoarthritis cartilage in vivo.

Jun Z ，Xinmeng J ，Yue L ，Zhi W ，Yan Z ，Tieyi Y ，Jiangan T ... -  《-》

Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia.

Li Y ，Zhang M ，Sheng M ，Zhang P ，Chen Z ，Xing W ，Bai J ，Cheng T ，Yang FC ，Zhou Y ... -  《-》