Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Immunity. 2010 Sep 24;33(3):313-25. doi: 10.1016/j.immuni.2010.09.001.
The molecular mechanisms underlying retinoic acid (RA) augmentation of T cell receptor (TCR) and transforming growth factor-β (TGF-β)-induced Foxp3 transcription and inhibition of the latter by cytokines such as IL-27 were here shown to be related processes involving modifications of baseline (TGF-β-induced) phosphorylated Smad3 (pSmad3) binding to a conserved enhancer region (enhancer I). RA augmentation involved the binding of retinoic acid receptor (RAR) and retinoid X receptor (RXR) to a dominant site in enhancer I and a subordinate site in the promoter. This led to increased histone acetylation in the region of the Smad3 binding site and increased binding of pSmad3. Cytokine (IL-27) inhibition involved binding of pStat3 to a gene silencer in a second conserved enhancer region (enhancer II) downstream from enhancer I; this led to loss of pSmad3 binding to enhancer I. Thus, control of accessibility and binding of pSmad3 provides a common framework for positive and negative regulation of TGF-β-induced Foxp3 transcription.
视黄酸（RA）增强 T 细胞受体（TCR）和转化生长因子-β（TGF-β）诱导的 Foxp3 转录的分子机制，以及细胞因子如 IL-27 对后者的抑制作用，其背后的机制涉及到对基线（TGF-β诱导）磷酸化 Smad3（pSmad3）与保守增强子区域（增强子 I）结合的修饰。RA 的增强涉及视黄酸受体（RAR）和视黄醇 X 受体（RXR）与增强子 I 中的显性位点和启动子中的次要位点结合。这导致 Smad3 结合位点区域的组蛋白乙酰化增加，pSmad3 结合增加。细胞因子（IL-27）的抑制涉及 pStat3 与增强子 II 中第二个保守增强子区域（增强子 II）中的基因沉默子结合，该区域位于增强子 I 下游；这导致 pSmad3 与增强子 I 的结合丢失。因此，pSmad3 的可及性和结合的控制为 TGF-β诱导的 Foxp3 转录的正调控和负调控提供了一个通用框架。
