Tetrandrine, an agonist of aryl hydrocarbon receptor, reciprocally modulates the activities of STAT3 and STAT5 to suppress Th17 cell differentiation.
Tetrandrine, a bisbenzylisoquinoline alkaloid constituent of the root of Stephania tetrandra S. Moore, was previously shown to suppress the differentiation of T helper 17 (Th17) cells and consequently ameliorate the collagen-induced arthritis (CIA) in mice by activating the aryl hydrocarbon receptor (AhR), but its underlying mechanism is incompletely understood. Here, we investigated how tetrandrine suppressed Th17 cell differentiation through the AhR pathway. The naïve CD4+T cells were stimulated with anti-CD3/CD28 for 72 hrs in the presence or absence of tetrandrine under the Th17-polarizing condition. Tetrandrine inhibited the phosphorylation of signal transducer and activator of transcription-3 (STAT3) and boosted the phosphorylation of STAT5, while it did not alter the expression levels of phospho-Janus kinase-1 (p-JAK1), p-JAK2, p-JAK3, and suppressor of cytokine signalling-3 (SOCS3). The tetrandrine-mediated inhibition of the Th17 cell differentiation could be diminished by the activator of STAT3 and the inhibitor of STAT5. Meanwhile, the effect of tetrandrine on the either STAT3 or STAT5 phosphorylation was almost completely reversed by the AhR antagonist CH223191 and the AhR knockdown. In CIA mice, tetrandrine decreased p-STAT3 levels and increased p-STAT5 levels, which could also be reversed by the AhR antagonist resveratrol administration. Furthermore, tetrandrine promoted the AhR binding to the STAT5, but not to the STAT3. The tetrandrine-induced inhibition of the STAT3 phosphorylation was diminished by the inhibitor of STAT5. Taken together, tetrandrine suppressed Th17 cell differentiation by reciprocally modulating the activities of STAT3 and STAT5 in an AhR-dependent manner.
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.
Zhifeng
Z
Wei
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
Yue
Y
Dai
D000818:Animals; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000378:metabolism; D015203:Reproducibility of Results; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058504:Th17 Cells / Q000166:cytology* / Q000187:drug effects
D044182:Benzylisoquinolines; D018336:Receptors, Aryl Hydrocarbon; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C009438:tetrandrine; D053612:Janus Kinases
STAT3; STAT5; Th17 cell differentiation; aryl hydrocarbon receptor; tetrandrine