伊卡帕Bzeta通过与ROR核受体合作来调节T(H) 17的发展
Kazuo Okamoto1, Yoshiko Iwai, Masatsugu Oh-Hora
1Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.
Nature
|April 13, 2010
概括
一种新型的转录因子,IkappaBzeta,对于开发产生互白素-17的辅助T (T) 细胞至关重要. 这一发现为自身免疫性疾病提供了新的治疗策略,如实验性自身免疫性脑膜炎 (EAE).
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 辅助T细胞17 (T(H) 17在自身免疫性疾病中至关重要.
- 17细胞的发育是由IL-6和TGF-β诱导的,其中包括RORgammat和RORalpha.
- 单独使用RORgammat或RORalpha可以在没有IL-6和TGF-β的情况下产生有限的IL-17.
研究的目的:
- 确定调节T(H) 17细胞发育的新型转录因子.
- 研究IkappaBzeta在T(H) 17分化和自身免疫性疾病中的作用.
- 阐明控制IL-17a基因表达的转录机制.
主要方法:
- 伊卡帕Bzeta在原始CD4 ((+) T细胞中的异胎表达.
- 在Nfkbiz的小鼠中分析了T(H) 17的发展.
- 实验性自身免疫脑膜炎 (EAE) 诱导和评估.
- 将Nfkbiz ((-/-) CD4(+) T细胞转移到Rag2 ((-/-) 的小鼠体内.
- ChIP测试评估IkappaBzeta与Il17a基因结合的情况.
主要成果:
- 伊卡帕Bzeta,与RORgammat或RORalpha一起,强烈诱导T(H) 17的发展,即使没有IL-6和TGF-β.
- Nfkbiz(-/-) 小鼠表现出T(H) 17发育受损以及对EAE的抗性.
- 在EAE耐药性中IkappaBzeta的T细胞内在功能通过细胞转移得到证实.
- 伊卡帕Bzeta直接与Il17a基因调节区域结合,增强IL-17a表达与RORs合作.
结论:
- 伊卡帕Bzeta是一个关键的转录因子,对T(H) 17细胞发育至关重要.
- 这项研究揭示了T(H) 17差异化背后的关键转录机制.
- 伊卡帕Bzeta代表了新型自身免疫性疾病治疗的潜在分子标.
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