School of Medicine, China Medical University, Taichung, Taiwan.
Department of Family Medicine, China Medical University Hsinchu Hospital, Hsinchu, Taiwan.
Environ Toxicol. 2020 Sep;35(9):991-997. doi: 10.1002/tox.22935. Epub 2020 May 13.
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, in which the immune system attacks synovial joint tissues. Interleukin (IL)-1β is a critical proinflammatory cytokine in RA progression. Sphingosine-1-phosphate (S1P), a platelet-derived lysophospholipid mediator, reportedly regulates osteoimmunology. Here, we investigated how S1P mediates IL-1β expression in osteoblasts. Our analysis of records from the Gene Expression Omnibus (GEO) database demonstrate higher levels of IL-1β in patients with RA compared with those with osteoarthritis. Stimulation of osteoblasts with S1P concentration dependently increased mRNA and protein expression of IL-1β. Elevations in IL-1β mRNA expression induced by S1P were reduced by the small interfering RNA (siRNA) against the S1P receptor. S1P also augmented JAK and STAT3 molecular cascades. We also found that JAK and STAT3 inhibitors and their siRNAs antagonized S1P-promoted IL-1β expression. Our results indicate that S1P promotes the expression of IL-1β in osteoblasts via the S1P receptor and the JAK and STAT3 signaling pathways.
类风湿关节炎（RA）是一种系统性自身免疫性炎症性疾病，其中免疫系统攻击滑膜关节组织。白细胞介素（IL）-1β是 RA 进展中的关键促炎细胞因子。鞘氨醇-1-磷酸（S1P）是一种血小板衍生的溶血磷脂介质，据报道它调节骨免疫学。在这里，我们研究了 S1P 如何在成骨细胞中调节 IL-1β 的表达。我们对基因表达综合数据库（GEO）记录的分析表明，与骨关节炎患者相比，RA 患者的 IL-1β 水平更高。S1P 浓度依赖性地刺激成骨细胞增加 IL-1β 的 mRNA 和蛋白表达。针对 S1P 受体的小干扰 RNA（siRNA）降低了 S1P 诱导的 IL-1β mRNA 表达的升高。S1P 还增强了 JAK 和 STAT3 分子级联反应。我们还发现 JAK 和 STAT3 抑制剂及其 siRNA 拮抗 S1P 促进的 IL-1β 表达。我们的结果表明，S1P 通过 S1P 受体以及 JAK 和 STAT3 信号通路促进成骨细胞中 IL-1β 的表达。
