Norisoboldine, an isoquinoline alkaloid, acts as an aryl hydrocarbon receptor ligand to induce intestinal Treg cells and thereby attenuate arthritis

• DOI: 10.1016/j.biocel.2016.03.014
• Publication Date: 2016-03-28T17:16:06Z
• Authors: Bei Tong; Xusheng Yuan; Yannong Dou; Xin Wu; Guixin Chou; Zhengtao Wang; Yufeng Xia; Yue Dai
• Keywords: Cell Nucleus; Male; 0303 health sciences; Active Transport, Cell Nucleus; Cell Differentiation; Ligands; T-Lymphocytes, Regulatory; Gene Expression Regulation, Enzymologic; 3. Good health; Arthritis, Rheumatoid; Intestines; Mice; 03 medical and health sciences; Alkaloids; Receptors, Aryl Hydrocarbon; Cytochrome P-450 CYP1A1; Animals; Th17 Cells; HSP90 Heat-Shock Proteins; Signal Transduction

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.