Arita Kojo, Tajima Mitsuru, Kobayashi Kazuma, Kimoto Yukari, Kemmochi Yusuke, Okamoto Yoshihisa, Katsuda Yoshiaki, Konishi Noriko, Yamaguchi Takayuki
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-13-2 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Biol Pharm Bull. 2025;48(7):1040-1048. doi: 10.1248/bpb.b25-00250.
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.
银屑病是一种慢性皮肤病，其症状显著降低患者的生活质量。银屑病的确切发病机制尚不清楚，但先前有关靶向17型辅助性T细胞（Th17）相关细胞因子和自身抗原的生物制剂的报道表明，抗原和细胞因子激活的Th17细胞均发挥重要作用。由于维甲酸相关孤儿受体γ（RORγ）被认为是Th17细胞的关键主调节因子，我们使用新型口服可用的RORγ拮抗剂JTE-151评估了RORγ的药理学抑制对抗原和细胞因子诱导的Th17细胞活化的影响。JTE-151在体外抑制了髓鞘少突胶质细胞糖蛋白（35-55）肽（MOG）刺激的Th17细胞诱导的白细胞介素-17A（IL-17A）和IL-22的产生，而抗IL-12/IL-23 p40抗体则没有。此外，JTE-151在体外也抑制了IL-23刺激的Th17细胞诱导的IL-17A和IL-22的产生。此外，JTE-151通过抑制Th17细胞活化，抑制了MOG免疫小鼠中MOG诱导的耳部肿胀，并改善了小鼠中IL-23诱导的皮炎。综上所述，我们表明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拮抗剂有可能成为治疗银屑病和其他Th17相关自身免疫性疾病的候选药物，并且RORγ的药理学抑制可能也比Th17相关细胞因子特异性生物制剂具有更广泛的作用。
