Yue Mengfan, Xia Yufeng, Shi Can, Guan Chunge, Li Yunfan, Liu Rui, Wei Zhifeng, Dai Yue
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
FEBS J. 2017 Sep;284(17):2786-2801. doi: 10.1111/febs.14147. Epub 2017 Jul 14.
Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its anti-arthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg·kg , i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells.
小檗碱是一种异喹啉生物碱，据报道口服给药可改善包括类风湿性关节炎在内的多种自身免疫性疾病。然而，由于其生物利用度极低，其作用机制仍然不明。鉴于肠道是体内最大的内分泌器官，小檗碱易于在肠道中蓄积，这一事实促使我们从肠道免疫抑制性神经肽的诱导方面探索其抗关节炎机制。在本研究中，小檗碱（200 mg·kg，灌胃）可改善大鼠胶原诱导的关节炎，表现为临床症状减轻、关节破坏减少，以及血液中Th17细胞频率和白细胞介素-17水平显著下调。相比之下，静脉注射小檗碱对大鼠关节炎没有影响，这意味着其抗关节炎作用依赖于肠道。进一步研究表明，口服小檗碱可选择性提高关节炎大鼠肠道和血清中5种肠道来源神经肽之一的可体松水平。胃饥饿素/生长激素促分泌素受体1（可体松受体的一种亚型）拮抗剂几乎完全消除了小檗碱对大鼠关节炎和Th17细胞反应的改善作用。在体外，小檗碱显示出适度促进神经细胞中可体松表达的能力，当神经细胞与肠内分泌细胞共培养以诱导自分泌/旁分泌环境时，这种能力会增强。总之，口服小檗碱通过抑制Th17细胞反应发挥抗关节炎作用，这与通过增强肠神经细胞和内分泌细胞之间的自分泌/旁分泌作用诱导肠道产生可体松密切相关。
