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

Abstract

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.

• Authors: Yuan Pan, Minzhen Wang, Xiaoqing Chen, Yuxi Chen, Siming Ai, Mei Wang, Wenru Su, Dan Liang
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 91 Pg. 107300 (Feb 2021) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 33383445 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• IL17A protein, human
• IL1F10 protein, human
• IL23R protein, human
• Interleukin-1
• Interleukin-17
• Interleukin-23
• PTGER2 protein, human
• PTGER4 protein, human
• Receptors, Interleukin
• Receptors, Prostaglandin E, EP2 Subtype
• Receptors, Prostaglandin E, EP4 Subtype
• Dinoprostone

Topics

• Adult
• Case-Control Studies
• Cells, Cultured
• Dinoprostone (metabolism)
• Feedback, Physiological
• Female
• Fibroblasts (immunology, metabolism)
• Gene Expression Regulation
• Graves Ophthalmopathy (diagnosis, genetics, immunology, metabolism)
• Humans
• Interleukin-1 (genetics, metabolism)
• Interleukin-17 (metabolism)
• Interleukin-23 (metabolism)
• Male
• Middle Aged
• Receptors, Interleukin (metabolism)
• Receptors, Prostaglandin E, EP2 Subtype (metabolism)
• Receptors, Prostaglandin E, EP4 Subtype (metabolism)
• Th17 Cells (drug effects, immunology, metabolism)
• Young Adult