Upregulation of lysine‐specific demethylase 6B aggravates inflammatory pain through H3K27me3 demethylation‐dependent production of TNF‐α in the dorsal root ganglia and spinal dorsal horn in rats

Abstract

AimsLysine‐specific demethylase 6B (KDM6B) serves as a key mediator of gene transcription. It regulates expression of proinflammatory cytokines and chemokines in variety of diseases. Herein, the role and the underlying mechanisms of KDM6B in inflammatory pain were studied.MethodsThe inflammatory pain was conducted by intraplantar injection of complete Freund's adjuvant (CFA) in rats. Immunofluorescence, Western blotting, qRT‐PCR, and chromatin immunoprecipitation (ChIP)‐PCR were performed to investigate the underlying mechanisms.ResultsCFA injection led to upregulation of KDM6B and decrease in the level of H3K27me3 in the dorsal root ganglia (DRG) and spinal dorsal horn. The mechanical allodynia and thermal hyperalgesia following CFA were alleviated by the treatment of intrathecal injection of GSK‐J4, and by microinjection of AAV‐EGFP‐KDM6B shRNA in the sciatic nerve or in lumbar 5 dorsal horn. The increased production of tumor necrosis factor‐α (TNF‐α) following CFA in the DRGs and dorsal horn was inhibited by these treatments. ChIP‐PCR showed that CFA‐induced increased binding of nuclear factor κB with TNF‐α promoter was repressed by the treatment of microinjection of AAV‐EGFP‐KDM6B shRNA.ConclusionsThese results suggest that upregulated KDM6B via facilitating TNF‐α expression in the DRG and spinal dorsal horn aggravates inflammatory pain.

Upregulation of KDM6B in the anterior cingulate cortex contributes to neonatal maternal deprivation-induced chronic visceral pain in mice

“…Recent studies have shown that KDM6B-mediated demethylation of H3K27me3 contributes to the promotion of chronic postsurgical pain (CPSP). 46 Notably, the inhibitor of KDM6B, GSK-J4, has shown significant attenuation of neuropathic pain in rats, 47 – 49 evidencing that KDM6B plays a critical role in the development and maintenance of neuropathic pain. This compelling evidence leads us to speculate that KDM6B may play a crucial regulatory role in the development of chronic visceral pain.…”