Sinomenine induces the generation of intestinal Treg cells and attenuates arthritis via activation of aryl hydrocarbon receptor.
Sinomenine (SIN), an anti-arthritis drug, has previously been proven to exert immunomodulatory activity in rats by inducing intestinal regulatory T-cells (Treg cells). Here, we assessed the effect of SIN on the generation and function of Treg cells in autoimmune arthritis, and the underlying mechanisms in view of aryl hydrocarbon receptor (AhR). The proportions of Treg cells and IL-17-producing T-cells (Th17 cells) differentiated from naive T-cells were analyzed by flow cytometric analysis. The AhR agonistic effect of SIN was tested by analyzing the activation of downstream signaling pathways and target genes. The dependence of intestinal Treg cell induction and arthritis alleviation by SIN on AhR activation was confirmed in a mouse collagen-induced arthritis (CIA) model. SIN promoted the differentiation and function of intestinal Treg cells in vitro. It induced the expression and activity of AhR target gene, promoted AhR/Hsp90 dissociation and AhR nuclear translocation, induced XRE reporter activity, and facilitated AhR/XRE binding in vitro, displaying the potential to be an agonist of AhR. In CIA mice, SIN induced the generation of intestinal Treg cells, and facilitated the immunosuppressive function of these Treg cells as shown by an adoptive transfer test. In addition, the induction of intestinal Treg cells and the anti-arthritic effect of SIN in CIA mice could be largely diminished by the AhR antagonist resveratrol. SIN attenuates arthritis by promoting the generation and function of Treg cells in an AhR-dependent manner.
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.|Institute of Botany, Jiangsu Province and Chinese Academy of Science (Nanjing Botanical Garden Mem. Sun Yat-Sen), Nanjing, Jiangsu, China.
Bei
B
Tong
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
Xusheng
X
Yuan
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
Yannong
Y
Dou
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
Xin
X
Wu
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
Yuhui
Y
Wang
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
Yufeng
Y
Xia
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
Yue
Y
Dai
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001168:Arthritis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008811:Mice, Inbred DBA; D009019:Morphinans / Q000494:pharmacology / Q000627:therapeutic use*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism
D018501:Antirheumatic Agents; D009019:Morphinans; D018336:Receptors, Aryl Hydrocarbon; C009271:sinomenine; D019363:Cytochrome P-450 CYP1A1