Results for “JMJD3” | Search PubMed

PubMed2026

Targeted Epigenetic Silencing of Jumonji Domain-Containing Protein 3 Alleviates Nuclear Factor-Kappa B-Mediated Inflammation in Familial Mediterranean Fever.

BACKGROUND: Familial Mediterranean fever (FMF) is an inherited autoinflammatory condition caused by variants in the MEFV gene encoding pyrin, the essential component of the NLRP3/NF-κB complex of inflammasomes. Deregulation of nuclear factor-kappa B (NF-κB), a key proinflammatory mediator, leads to chronic inflammation in autoinflammatory/autoimmune diseases. Epigenetic modulation offers a new approach to regulate inflammasome activity, with Jumonji domain-containing protein 3 (JMJD3) being a promising target for managing inflammatory illnesses. GSK-J4 is a selective inhibitor of JMJD3, restricting pro-inflammatory cytokines and inflammation. AIM: Our research aimed to elucidate the role of JMJD3 and the NF-κB-JMJD3 signaling pathways in regulating inflammation in an in vitro model, and to investigate GSK-J4's effect in inhibiting inflammasome activation in primed peripheral blood mononuclear cells (PBMCs) isolated from FMF cases. METHODS: PBMCs were cultured and primed with LPS, and then treated with GSK-J4. JMJD3 knockdown was achieved using siRNA interference. Cellular inflammatory dynamics were assessed by Western blotting (WB) and ELISA. The qRT-PCR was used for gene expression quantification. Untreated cells served as a negative control. RESULTS: Our results showed significantly downregulated gene expression of NF-κB, NLRP3, and inflammatory cytokines in GSK-J4-treated cells compared to untreated cells, as confirmed by ELISA. WB reported a reduction of NF-κB in induced cells following GSK-J4 treatment. Knocking down JMJD3 also showed decreased levels of JMJD3, NF-κB, and inflammatory cytokines, indicating its proinflammatory role. CONCLUSION: The study showed that selective inhibition or silencing of JMJD3 significantly suppressed the inflammasome in FMF cases, suggesting its role as a therapeutic target for alleviating inflammation in various autoinflammatory diseases.

Humans↗

PubMed2014

Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia.

T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.

Animals↗