期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 101, 期 5, 页码 1181-1190出版社
WILEY
DOI: 10.1189/jlb.2A0416-187RR
关键词
Tr 1 cells; signaling; gene regulation
资金
- Aide a la Recherche sur la Sclerose En Plaques Foundation (ARSEP)
- Institut Pasteur
- Centre National de la Recherche Scientifique (CNRS)
- Pasteur-Paris University (PPU) International Ph.D. Program
- Immunology Department of the Institut Pasteur
- ARSEP
Type I IFN can exert pro- and anti-inflammatory activities in the immune system. Here, we have investigated the mechanism by which IFN-alpha enhances early expression of the anti-inflammatory cytokine IL-10 in human CD45RA(+)CD4(+) T cells. With the use of transcriptomic and biochemical approaches, we found distinct and combined contributions of the IFN and the TCR signaling pathways to the induction of STAT1/2/3 and the basic leucine zipper activating transcription factor-like (BATF) family members. Moreover, IFN-induced STAT3 phosphorylation was prolonged by the TCR response, whereas IFN-induced STAT2 phosphorylation was of long duration. With the use of RNA interference (RNAi), we identified STAT3 as the major actor and STAT2 as a contributor of the IFN action on IL-10. Upon TCR/IFN costimulation, STAT3 directly bound at the IL-10 conserved noncoding sequence (CNS)-9, an enhancer element known to recruit BATF in CD4 T cells. The cosilencing of the 3 BATFs resulted in an overall reduction of IL-10 expression, but the promoting activity of IFN-alpha was retained. These results support the notion that the IFN action is indexed on BATF function and provide evidence for a cooperation between BATFs and STAT3, the latter being activated via early IFN and delayed TCR effects.
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