期刊
JOURNAL OF AUTOIMMUNITY
卷 39, 期 4, 页码 428-440出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2012.07.007
关键词
Autoimmunity; CD4(+) Th17 cells; Il17a promoter; NR2F6; NFAT; ROR gamma t
类别
资金
- FWF Austrian Science Fund [P23537-B13, SFB-021, MCBO-DK]
- European Community [HEALTH-F4-2008-201106]
- Medical University Innsbruck grant [MUI-Start1 2010011001]
- Austrian Science Fund (FWF) [P23537] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [P 23537] Funding Source: researchfish
Interleukin-17A (IL-17A) is the signature cytokine produced by Th17 CD4(+) T cells and has been tightly linked to autoimmune pathogenesis. In particular, the transcription factors NFAT and ROR gamma t are known to activate Il17a transcription, although the detailed mechanism of action remains incompletely understood. Here, we show that the nuclear orphan receptor NR2F6 can attenuate the capacity of NFAT to bind to critical regions of the Il17a gene promoter. In addition, because NR2F6 binds to defined hormone response elements (HREs) within the Il17a locus, it interferes with the ability of ROR gamma t to access the DNA. Consistently, NFAT and ROR gamma t binding within the Il17a locus were enhanced in Nr2f6-deficient CD4(+) Th17 cells but decreased in Nr2f6-overexpressing transgenic CD4(+) Th17 cells. Taken together, our findings uncover an example of antagonistic regulation of Il17a transcription through the direct reciprocal actions of NR2F6 versus NFAT and ROR gamma t. (C) 2012 Elsevier Ltd. All rights reserved.
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