title: Norisoboldine, an isoquinoline alkaloid, acts as an aryl hydrocarbon receptor ligand to induce intestinal Treg cells and thereby attenuate arthritis.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  Oral NOR induces the generation of intestinal Treg cells by the activation of AhR, and thereby exerts anti-arthritic effect.
authors.affiliation: 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.
authors.forename: Bei
authors.initials: B
authors.lastname: Tong
authors.affiliation: 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.
authors.forename: Xusheng
authors.initials: X
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Yannong
authors.initials: Y
authors.lastname: Dou
authors.affiliation: 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Guixin
authors.initials: G
authors.lastname: Chou
authors.affiliation: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xia
authors.affiliation: 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.
authors.forename: Yue
authors.initials: Y
authors.lastname: Dai
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000470:Alkaloids / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000276:immunology*; D008024:Ligands; D008297:Male; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects
chemical_list: D000470:Alkaloids; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; C464745:norisoboldine; D019363:Cytochrome P-450 CYP1A1
keywords: Aryl hydrocarbon receptor; Collagen-induced arthritis; Differentiation; Norisoboldine; Regulatory T cells