Bei Tong1, Xusheng Yuan1, Yannong Dou1, Xin Wu1, Guixin Chou2, Zhengtao Wang2, Yufeng Xia3, Yue Dai4. 1. Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. 2. Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. 3. Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: yfxiacpu@126.com. 4. Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: yuedaicpu@hotmail.com.
Abstract
OBJECTIVE: Norisoboldine (NOR), an isoquinoline alkaloid with very poor oral bioavailability, was previously proven to have a unique anti-arthritis activity in rats by inducing intestinal Treg cells. Herein, we explored its underlying mechanism in view of aryl hydrocarbon receptor (AhR). METHODS: The differentiation of regulatory T cells (Treg cells) and IL-17-producing T cells (Th17 cells) from naïve T cells was analyzed in vitro. The key role of AhR was ascertained using siRNA transfection. AhR agonistic effect was verified based on the activation of downstream signaling pathway and target genes. The correlation between AhR activation and Treg cell induction as well as pathological changes of joints was confirmed in collagen-induced arthritis (CIA) mouse model. RESULTS: NOR promoted intestinal Treg cell differentiation and function in an AhR-dependent manner. It acted as an AhR agonist, as evidenced by induction of CYP1A1 expression and activity, promotion of AhR/Hsp90 dissociation and AhR nuclear translocation, induction of XRE reporter activity, and facilitation of AhR/XRE binding. In CIA mice, NOR exerted substantial anti-arthritic effect through enhancing AhR activation in intestinal tissues and inducing intestinal Treg cell generation, which could be largely abolished by resveratrol (a antagonist of AhR). An adoptive transfer of Treg cells from NOR-treated mice could successfully alleviate arthritis symptoms in CIA mice. CONCLUSION: Oral NOR induces the generation of intestinal Treg cells by the activation of AhR, and thereby exerts anti-arthritic effect.
OBJECTIVE:Norisoboldine (NOR), an isoquinoline alkaloid with very poor oral bioavailability, was previously proven to have a unique anti-arthritis activity in rats by inducing intestinal Treg cells. Herein, we explored its underlying mechanism in view of aryl hydrocarbon receptor (AhR). METHODS: The differentiation of regulatory T cells (Treg cells) and IL-17-producing T cells (Th17 cells) from naïve T cells was analyzed in vitro. The key role of AhR was ascertained using siRNA transfection. AhR agonistic effect was verified based on the activation of downstream signaling pathway and target genes. The correlation between AhR activation and Treg cell induction as well as pathological changes of joints was confirmed in collagen-induced arthritis (CIA) mouse model. RESULTS:NOR promoted intestinal Treg cell differentiation and function in an AhR-dependent manner. It acted as an AhR agonist, as evidenced by induction of CYP1A1 expression and activity, promotion of AhR/Hsp90 dissociation and AhR nuclear translocation, induction of XRE reporter activity, and facilitation of AhR/XRE binding. In CIA mice, NOR exerted substantial anti-arthritic effect through enhancing AhR activation in intestinal tissues and inducing intestinal Treg cell generation, which could be largely abolished by resveratrol (a antagonist of AhR). An adoptive transfer of Treg cells from NOR-treated mice could successfully alleviate arthritis symptoms in CIA mice. CONCLUSION: Oral NOR induces the generation of intestinal Treg cells by the activation of AhR, and thereby exerts anti-arthritic effect.
Authors: Jhimmy Talbot; Raphael S Peres; Larissa G Pinto; Rene D R Oliveira; Kalil A Lima; Paula B Donate; Jaqueline R Silva; Bernard Ryffel; Thiago M Cunha; José C Alves-Filho; Foo Y Liew; Paulo Louzada-Junior; Fernando de Queiroz Cunha Journal: Arthritis Res Ther Date: 2018-06-08 Impact factor: 5.156
Authors: Alzahrani Abdullah; Mohammed Maged; Ibrahim Hairul-Islam M; Alwassil Osama I; Habash Maha; Alfuwaires Manal; Hanieh Hamza Journal: PLoS One Date: 2019-04-26 Impact factor: 3.240