Elevated IL-38 inhibits IL-23R expression and IL-17A production in thyroid-associated ophthalmopathy

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.