Experimental Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Natural Medicine, School of Pharmacy, Fudan University, Shanghai, China.
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Pharmacol Res. 2020 Jan;151:104513. doi: 10.1016/j.phrs.2019.104513. Epub 2019 Nov 6.
The suppression of the abnormal systemic immune response constitutes a primary strategy for treatment of rheumatoid arthritis (RA); toward this end, the identification of natural compounds with immunosuppressive activity represents a promising strategy for RA drug discovery. Cinnamtannin D1 (CTD-1), a polyphenolic compound isolated from Cinnamomum tamala, was previously reported to possess good immunosuppressive activity. However, the beneficial effect of CTD-1 on RA is currently unknown. The aim of this study was to evaluate the anti-arthritic effect of CTD-1 in collagen-induced arthritis (CIA) mice and clarify the underlying mechanisms. CTD-1 treatment significantly alleviated the severity of CIA mice, affording reduced clinical scores and paw swelling, along with reduced inflammatory cell infiltration and cartilage damage in the joints; in addition, the serum levels of IL-17, IL-6, and IL-1β were decreased whereas those of TGF-β and IL-10 were increased. CTD-1-treated mice exhibited lower frequency of Th17 cells and higher frequency of Treg cells compared to those in untreated mice, indicating that the balance of Th17/Treg cells may serve as the target for CTD-1. Consistent with this, in ex vivo assays, CTD-1 inhibited Th17 cell differentiation through the downregulation of phospho-STAT3/RORγt, whereas it promoted Treg differentiation by upregulating phospho-STAT5/Foxp3 in response to the stimulation of collagen type II. Moreover, in an in vitro naïve CD4 T cell differentiation assay, CTD-1 directly inhibited Th17 cell differentiation and promoted Treg differentiation, suggesting that CTD-1 regulated the balance of Th17 and Treg cells to inhibit excessive immune response. Furthermore, the regulation effect of CTD-1 on Th17 and Treg cells was dependent on Ahr expression, as this effect was abolished when Ahr was knocked down and was impaired when Ahr was overexpressed. Together, our results indicated that CTD-1 treatment benefits CIA mice by regulating Th17 and Treg differentiation through the inhibition of AHR expression, and suggested a potential application of CTD-1 toward RA treatment.
抑制异常的系统性免疫反应是治疗类风湿关节炎（RA）的主要策略；为此，鉴定具有免疫抑制活性的天然化合物代表了 RA 药物发现的一种有前途的策略。肉桂单宁 D1（CTD-1）是从肉桂树中分离得到的一种多酚化合物，先前有报道称其具有良好的免疫抑制活性。然而，CTD-1 对 RA 的有益作用目前尚不清楚。本研究旨在评估 CTD-1 对胶原诱导性关节炎（CIA）小鼠的抗关节炎作用，并阐明其潜在机制。CTD-1 治疗显著减轻 CIA 小鼠的严重程度，降低临床评分和爪肿胀，减少关节内炎症细胞浸润和软骨损伤；此外，血清中 IL-17、IL-6 和 IL-1β 的水平降低，而 TGF-β 和 IL-10 的水平升高。与未治疗的小鼠相比，CTD-1 治疗的小鼠 Th17 细胞频率降低，Treg 细胞频率升高，表明 Th17/Treg 细胞的平衡可能是 CTD-1 的作用靶点。与此一致的是，在体外实验中，CTD-1 通过下调磷酸化 STAT3/RORγt 抑制 Th17 细胞分化，而通过上调磷酸化 STAT5/Foxp3 促进 Treg 分化，以响应胶原 II 的刺激。此外，在体外幼稚 CD4 T 细胞分化实验中，CTD-1 直接抑制 Th17 细胞分化并促进 Treg 分化，表明 CTD-1 通过调节 Th17 和 Treg 细胞的平衡来抑制过度免疫反应。此外，CTD-1 对 Th17 和 Treg 细胞的调节作用依赖于 Ahr 的表达，当 Ahr 被敲低时，这种作用被消除，当 Ahr 过表达时，这种作用受损。综上所述，我们的研究结果表明，CTD-1 通过抑制 AHR 表达调节 Th17 和 Treg 细胞分化，有益于 CIA 小鼠，并提示 CTD-1 在 RA 治疗中的潜在应用。
