STAT6 inhibits TGF-β1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor
STAT6 inhibits TGF-β1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor
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DOI：
10.1074/jbc.m801123200
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发表时间：
2008-05-30
影响因子：
4.8
通讯作者：
Kobayashi, Takashi
中科院分区：
文献类型：
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作者：
Takaki, Hiromi;Ichiyama, Kenji;Kobayashi, Takashi
已经显示，转化生长因子β（TGF-β 1）在从初始CD 4（+）T细胞产生CD 4（+）CD 25（+）Foxp 3（+）诱导型调节性T细胞（iTclad）中是关键的。然而，与天然的TGF-beta 1相反，TGF-β 1诱导的iTGF-beta 1迅速失去Foxp 3表达和抑制活性。我们发现TGF-β 1诱导的Foxp 3水平通过加入抗白细胞介素4（IL-4）抗体或通过STAT 6基因缺失得以维持。因此，IL-4是Foxp 3诱导的重要抑制因子，辅助性T细胞2的发育是长期培养过程中iTreg消失的主要原因。使用在EL 4细胞和原代T细胞中的启动子分析，我们鉴定了含有STAT 6结合位点的沉默子区域。STAT 6与该位点的结合减少了TGF-β 1介导的Foxp 3启动子激活和染色质修饰。还已经显示，视黄酸在TGF-β 1的存在下抑制由TGF-β 1诱导的Foxp 3的损失，减少STAT 6与Foxp 3启动子的结合并增强组蛋白乙酰化，从而逆转IL-4的作用。我们提出，中和IL-4的拮抗剂可能是一种新的策略，以促进诱导型Treg细胞的产生和促进耐受性的Th 2为主的疾病，如过敏。
It has been shown that transforming growth factor beta (TGF-beta 1) is critical in the generation of CD4(+)CD25(+)Foxp3(+) -inducible regulatory T cells (iTregs) from naive CD4(+)T cells. However, in contrast to natural Tregs, TGF-beta 1-induced iTregs rapidly lose both Foxp3 expression and suppression activity. We found that TGF-beta 1-induced Foxp3 levelswere maintained by the addition of the anti-interleukin 4 (IL-4) antibody or by STAT6 gene deletion. Thus, IL-4 is an important suppressor of Foxp3 induction, and T helper 2 development is a major cause for the disappearance of iTreg during long culture. Using promoter analysis in EL4 cells and primary T cells, we identified a silencer region containing a STAT6 binding site. STAT6 binding to this site reduced TGF-beta 1-mediated Foxp3 promoter activation and chromatin modification. Retinoic acid has also been shown to suppress loss of Foxp3 induced by TGF-beta 1 Retinoic acid in the presence of TGF-beta 1 reduced STAT6 binding to the Foxp3 promoter and enhanced histone acetylation, thereby reverting the effect of IL-4. We propose that antagonistic agents for neutralizing IL-4 could be a novel strategy to facilitate inducible Treg cell generation and the promotion of tolerance in Th2-dominated diseases such as allergy.