Pharmacological potential of the histone demethylase inhibitor GSK-J4 in mitigating NF-κB-mediated inflammatory cascades associated with autoimmune disorders.

Inflammasome-related sterile inflammation is a leading cause of several autoimmune and rheumatic disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD). Although the exact causes of rheumatic diseases remain unclear, it is evident that ongoing inflammatory reactions are the main factors driving their development. Jumonji domain-containing protein-3 (JMJD3) is an epigenetic modifier that can strongly promote the inflammatory process in many diseases by impacting the Nuclear Factor-κB (NF-κB) signaling. Meanwhile, GSK-J4 has been identified as a selective inhibitor of JMJD3. Therefore, our study aimed at exploring the effects of JMJD3 inhibition by GSK-J4 on inflammasome activation and oxidative stress release in lipopolysaccharide (LPS)-primed patient-derived adherent mononuclear cells of different autoimmune diseases: RA, SLE, and IBD. The inflammatory response was evaluated prior to and following the GSK-J4-cell treatment by assessment of gene and protein expression of inflammatory factors using qRT-PCR and Western blot, respectively. Additionally, cytokine and nitric oxide release in culture supernatants was measured using enzyme-linked immunosorbent assay (ELISA). Our results showed a significant correlation between the inhibition of JMJD3 and the attenuation of inflammatory signaling pathways through reduced NF-κB activation, diminished expression of pro-inflammatory cytokines, and decreased inflammatory stress response. These findings supported the idea that epigenetic modification is a crucial mechanism for priming the inflammasome activation in various autoimmune diseases, confirming the potential of epigenetic factors as prospective therapeutic targets for immune-mediated inflammatory diseases.