{"title":"药物抑制RORγ改善抗原和细胞因子激活的Th17细胞诱导的皮肤炎症。","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":"{\"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}","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
摘要
银屑病是一种慢性皮肤病,其症状明显降低患者的生活质量。银屑病的详细发病机制尚不清楚,但先前关于靶向T辅助型17 (Th17)相关细胞因子和自身抗原的生物制剂的报道表明,抗原和细胞因子活化的Th17细胞都起重要作用。由于类视黄酮相关孤儿受体-γ (RORγ)被认为是Th17细胞的关键主调节剂,我们使用JTE-151(一种新型口服RORγ拮抗剂)评估了药理学抑制RORγ对抗原和细胞因子激活Th17细胞的影响。JTE-151能抑制髓鞘少突胶质细胞糖蛋白(35-55)肽(MOG)刺激的Th17细胞产生白细胞介素17a (IL-17A)和IL-22,而抗il -12/ il - 23p40抗体则无此作用。此外,JTE-151还能抑制il -23刺激的Th17细胞在体外诱导的IL-17A和IL-22的产生。此外,JTE-151通过抑制Th17细胞活化,抑制mog免疫小鼠的耳部肿胀,改善il -23诱导的小鼠皮炎。综上所述,我们发现JTE-151对RORγ的药理学抑制抑制了抗原和细胞因子诱导的Th17细胞的活化,并且还改善了Th17细胞活化后的皮肤炎症。这些结果表明,包括JTE-151在内的RORγ拮抗剂有潜力成为治疗牛皮癣和其他th17相关自身免疫性疾病的候选药物,并且对RORγ的药理学抑制也可能比th17相关细胞因子特异性生物制剂具有更广泛的作用。
Pharmacological Inhibition of RORγ Ameliorates Skin Inflammation Induced by Both Antigen- and Cytokine-Activated Th17 Cells.
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.
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