Department of Pharmacology, Shanghai Key Laboratory of Bioactive Small Molecules, School of Pharmacy, Fudan University, Shanghai, 201203, China.
State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China.
Cell Mol Immunol. 2019 Aug;16(8):694-705. doi: 10.1038/s41423-018-0037-8. Epub 2018 May 29.
Cystathionine-γ-lyase (CSE), an enzyme associated with hydrogen sulfide (HS) production, is an important endogenous regulator of inflammation. Jumonji domain-containing protein 3 (JMJD3) is implicated in the immune response and inflammation. Here, we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis (RA). Upregulated CSE and JMJD3 were identified in synovial fibroblasts (SFs) from RA patients as well as in the joints of arthritic mice. Knocking down CSE augmented inflammation in IL-1β-induced SFs by increasing JMJD3 expression. In addition, CSE mice with collagen-induced arthritis (CIA) developed severe joint inflammation and bone erosion. Conversely, overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1β-treated SFs. Furthermore, JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1β-treated SFs, mainly by controlling the methylation status of H3K27me3 at the promoter of its target genes. GSK-J4 markedly attenuated the severity of arthritis in CIA mice. In conclusion, suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.
胱硫醚-γ-裂解酶（CSE）是一种与硫化氢（HS）产生相关的酶，是炎症的重要内源性调节剂。含 JMJD 结构域蛋白 3（JMJD3）与免疫反应和炎症有关。在这里，我们研究了 JMJD3 对类风湿关节炎（RA）中内源性 CSE 介导的炎症的潜在贡献。在 RA 患者的滑膜成纤维细胞（SFs）以及关节炎小鼠的关节中，均发现 CSE 和 JMJD3 上调。敲低 CSE 通过增加 JMJD3 的表达，增强了 IL-1β诱导的 SFs 中的炎症。此外，胶原诱导关节炎（CIA）的 CSE 小鼠表现出严重的关节炎症和骨侵蚀。相反，过表达 CSE 通过转录因子 Sp-1 抑制 JMJD3 的表达，同时减少 IL-1β 处理的 SFs 中的炎症。此外，JMJD3 沉默或 JMJD3 抑制剂 GSK-J4 的给药显著降低了 IL-1β 处理的 SFs 中的炎症反应，主要是通过控制其靶基因启动子处 H3K27me3 的甲基化状态。GSK-J4 显著减轻 CIA 小鼠关节炎的严重程度。总之，转录因子 Sp-1 抑制 JMJD3 的表达可能是 CSE 负调控炎症反应和减轻 RA 进展的能力的原因。
