Department of Biology, Changwon National University, Changwon, Kyungnam 641-773, South Korea.
Toxicol Lett. 2013 Jul 4;220(2):109-17. doi: 10.1016/j.toxlet.2013.04.016. Epub 2013 Apr 29.
Although AhR activation regulates CD4T cell differentiation, how it works has yet to be elucidated. In the present study, using in vitro Th17 differentiation model, we examined effects of AhR activation by indoxyl 3-sulfate (I3S), a uremic toxin, on Th17 differentiation and investigated underlying mechanisms. I3S increased expression of RORγt, the master transcription factor for Th17 differentiation, and stimulated Th17 differentiation, in a comparative manner as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a prototypical AhR ligand. Activation of STAT3, which is phosphorylated by the IL-6 signaling pathways and thus is necessary for Th17 differentiation, was strongly stimulated by I3S and TCDD. Phosphorylation of c-Src, which was shown to be activated by AhR ligands, was also increased by I3S and TCDD, and blocking of c-Src activity by 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine (PP2) inhibited phosphorylation of both c-Src and STAT3, raising a possibility that stimulatory activities of I3S and TCDD on Th17 differentiation could be exerted via increased phosphorylation of c-Src, which in turn stimulates STAT3 activation. Finally, we found that I3S worsened experimental autoimmune encephalomyelitis (EAE), which is primarily mediated by Th17 cells, enhancing the frequency of IL-17-producing cells in draining lymph nodes.
虽然 AhR 激活可调节 CD4T 细胞分化，但具体机制仍不清楚。本研究采用体外 Th17 分化模型，探讨了尿毒症毒素吲哚硫酸（I3S）对 Th17 分化的影响及其作用机制。结果表明，I3S 可增加 Th17 分化的主转录因子 RORγt 的表达，并以与 2,3,7,8-四氯二苯并对二恶英（TCDD）类似的方式刺激 Th17 分化。I3S 和 TCDD 强烈刺激由 IL-6 信号通路磷酸化的 STAT3 激活，而磷酸化的 STAT3 是 Th17 分化所必需的。c-Src 也被 AhR 配体激活，其磷酸化也被 I3S 和 TCDD 增加，而 4-氨基-5-(4-氯苯基)-7-(叔丁基)吡唑并[3,4-d]嘧啶（PP2）抑制 c-Src 的活性可抑制 c-Src 和 STAT3 的磷酸化，提示 I3S 和 TCDD 对 Th17 分化的刺激作用可能通过增加 c-Src 的磷酸化来发挥作用，进而刺激 STAT3 的激活。最后，我们发现 I3S 可加重实验性自身免疫性脑脊髓炎（EAE），EAE 主要由 Th17 细胞介导，增加引流淋巴结中产生 IL-17 的细胞的频率。
