IL-23/IL-23R and PGE₂/EP2+EP4 have been recognized as crucial signals that promote Th17 differentiation in many autoimmune diseases, including thyroid-associated ophthalmopathy (TAO). However, the interactive role of IL-23R in IL-23/Th17 signaling and PGE₂/Th17 signaling has not been clarified in TAO. Furthermore, the role of IL-38, a novel anti-inflammatory cytokine, has not been explored in TAO. Thus, we aimed to investigate the roles of IL-23R and IL-38 in the pathogenesis of TAO. Activated peripheral blood mononuclear cells (PBMCs) were cultured with or without IL-23 and PGE₂. The results showed that IL-23R and IL-17A were upregulated to different degrees and reached the highest levels with both stimuli, indicating that IL-23 induced PBMCs to secrete PGE₂, which further boosted the proportion of IL-23R+CD4+T cells to promote IL-17A secretion. Pretreatment with antagonists aimed at EP2/EP4 receptors diminished PGE₂-induced upregulation of IL-23R and IL-17A. IL-38 in TAO patients was increased. Activated orbital fibroblasts (OFs) and PBMCs were pretreated with different concentrations of IL-38. IL-23R and IL-17A expression in circulating PBMCs and IL-6 and IL-8 in resident OFs were suppressed by IL-38 at relatively low concentrations. Our findings suggest that the feedback loop of IL-23/IL-23R/PGE₂/EP2+EP4/IL-23R/IL-17A plays a significant role in the pathogenesis of TAO and that IL-23R is one of the key targets. Increased IL-38 in TAO could not only inhibit the expression of IL-23R and IL-17A in PBMCs but also suppress inflammation in OFs. Therapies targeting IL-23R may be effective, and IL-38 could be a potential therapeutic approach for TAO.

IL-23 / IL-23R和PGE ₂ / EP2 + EP4已被认为是在许多自身免疫性疾病（包括甲状腺相关性眼病）中促进Th17分化的关键信号。然而，在TAO中尚未阐明IL-23R在IL-23 / Th17信号传导和PGE ₂ / Th17信号传导中的相互作用。此外，尚未在TAO中探索新型抗炎细胞因子IL-38的作用。因此，我们旨在研究IL-23R和IL-38在TAO发病机理中的作用。在有或没有IL-23和PGE _2的情况下培养活化的外周血单核细胞（PBMC）。结果表明，IL-23R和IL-17A在两种刺激下均不同程度上调并达到最高水平，表明IL-23诱导PBMC分泌PGE。_{如图2所示}，其进一步增加了IL-23R + CD4 + T细胞的比例以促进IL-17A的分泌。用针对EP2 / EP4受体的拮抗剂进行的预处理减少了PGE ₂诱导的IL-23R和IL-17A的上调。TAO患者的IL-38升高。活化的眼眶成纤维细胞（OFs）和PBMC用不同浓度的IL-38预处理。IL-38在相对低的浓度下可抑制循环PBMC中的IL-23R和IL-17A表达以及常驻OF中的IL-6和IL-8。我们的发现表明，IL-23 / IL-23R / PGE ₂的反馈回路/ EP2 + EP4 / IL-23R / IL-17A在TAO的发病机制中起重要作用，而IL-23R是关键靶标之一。TAO中IL-38的升高不仅可以抑制PBMCs中IL-23R和IL-17A的表达，而且可以抑制OFs中的炎症。靶向IL-23R的疗法可能是有效的，而IL-38可能是TAO的潜在治疗方法。