{"title":"Pharmacological Inhibition of RORγ Ameliorates Skin Inflammation Induced by Both Antigen- and Cytokine-Activated Th17 Cells.","authors":"Kojo Arita, Mitsuru Tajima, Kazuma Kobayashi, Yukari Kimoto, Yusuke Kemmochi, Yoshihisa Okamoto, Yoshiaki Katsuda, Noriko Konishi, Takayuki Yamaguchi","doi":"10.1248/bpb.b25-00250","DOIUrl":null,"url":null,"abstract":"<p><p>Psoriasis is a chronic skin disease, and its symptoms markedly decrease patients' QOL. The detailed pathogenesis of psoriasis remains unclear, but previous reports about biologics targeting T helper type 17 (Th17)-related cytokines and autoantigens have suggested that both antigen- and cytokine-activated Th17 cells have important roles. Since retinoid-related orphan receptor-γ (RORγ) is recognized as the key master regulator of Th17 cells, we assessed the effects of pharmacological inhibition of RORγ using JTE-151, a novel orally available RORγ antagonist, on the activation of Th17 cells by antigen and cytokine. JTE-151 suppressed the production of both interleukin-17A (IL-17A) and IL-22 induced by myelin oligodendrocyte glycoprotein (35-55) peptide (MOG)-stimulated Th17 cells in vitro, whereas anti-IL-12/IL-23 p40 antibody did not. Moreover, JTE-151 also suppressed the production of both IL-17A and IL-22 induced by IL-23-stimulated Th17 cells in vitro. Furthermore, JTE-151 suppressed MOG-induced ear swelling in MOG-immunized mice and ameliorated IL-23-induced dermatitis in mice through the inhibition of Th17 cell activation. Taken together, we showed that pharmacological inhibition of RORγ by JTE-151 suppressed the activation of Th17 cells induced by both antigen and cytokine, and that it also ameliorated skin inflammation following Th17 cell activation. These results suggest that RORγ antagonists, including JTE-151, have the potential to become drug candidates for fighting psoriasis and other Th17-related autoimmune diseases, and that pharmacological inhibition of RORγ may also have broader effects than Th17-related cytokine-specific biological agents.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 7","pages":"1040-1048"},"PeriodicalIF":1.7000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biological & pharmaceutical bulletin","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1248/bpb.b25-00250","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Psoriasis is a chronic skin disease, and its symptoms markedly decrease patients' QOL. The detailed pathogenesis of psoriasis remains unclear, but previous reports about biologics targeting T helper type 17 (Th17)-related cytokines and autoantigens have suggested that both antigen- and cytokine-activated Th17 cells have important roles. Since retinoid-related orphan receptor-γ (RORγ) is recognized as the key master regulator of Th17 cells, we assessed the effects of pharmacological inhibition of RORγ using JTE-151, a novel orally available RORγ antagonist, on the activation of Th17 cells by antigen and cytokine. JTE-151 suppressed the production of both interleukin-17A (IL-17A) and IL-22 induced by myelin oligodendrocyte glycoprotein (35-55) peptide (MOG)-stimulated Th17 cells in vitro, whereas anti-IL-12/IL-23 p40 antibody did not. Moreover, JTE-151 also suppressed the production of both IL-17A and IL-22 induced by IL-23-stimulated Th17 cells in vitro. Furthermore, JTE-151 suppressed MOG-induced ear swelling in MOG-immunized mice and ameliorated IL-23-induced dermatitis in mice through the inhibition of Th17 cell activation. Taken together, we showed that pharmacological inhibition of RORγ by JTE-151 suppressed the activation of Th17 cells induced by both antigen and cytokine, and that it also ameliorated skin inflammation following Th17 cell activation. These results suggest that RORγ antagonists, including JTE-151, have the potential to become drug candidates for fighting psoriasis and other Th17-related autoimmune diseases, and that pharmacological inhibition of RORγ may also have broader effects than Th17-related cytokine-specific biological agents.
期刊介绍:
Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.) began publication in 1978 as the Journal of Pharmacobio-Dynamics. It covers various biological topics in the pharmaceutical and health sciences. A fourth Society journal, the Journal of Health Science, was merged with Biol. Pharm. Bull. in 2012.
The main aim of the Society’s journals is to advance the pharmaceutical sciences with research reports, information exchange, and high-quality discussion. The average review time for articles submitted to the journals is around one month for first decision. The complete texts of all of the Society’s journals can be freely accessed through J-STAGE. The Society’s editorial committee hopes that the content of its journals will be useful to your research, and also invites you to submit your own work to the journals.