کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2599179 1133194 2013 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Indoxyl 3-sulfate stimulates Th17 differentiation enhancing phosphorylation of c-Src and STAT3 to worsen experimental autoimmune encephalomyelitis
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
Indoxyl 3-sulfate stimulates Th17 differentiation enhancing phosphorylation of c-Src and STAT3 to worsen experimental autoimmune encephalomyelitis
چکیده انگلیسی


• Indoxyl 3-sulfate (I3S), a uremic toxin, activates AhR during Th17 differentiation.
• I3S stimulates Th17 differentiation and increases RORγt expression.
• I3S increases phosphorylation of STAT3 and c-Src.
• Blocking of c-Src activity inhibits I3S-mediated STAT3 activation.
• I3S worsens EAE, probably via stimulating Th17 differentiation in vivo.

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology Letters - Volume 220, Issue 2, 4 July 2013, Pages 109–117
نویسندگان
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