School of Bioscience, Indian Institute of Technology Kharagpur, India.
School of Bioscience, Indian Institute of Technology Kharagpur, India.
Cytokine. 2024 Jan;173:156440. doi: 10.1016/j.cyto.2023.156440. Epub 2023 Nov 20.
17-β Estradiol (E2) has long standing known functions in regulating human physiology as well as immune system. E2 is known to elicit a protective role against experimental autoimmune encephalomyelitis (EAE) and has been used as a drug for treatment against multiple sclerosis. Moreover, E2 regulates the adaptive immune system by directly affecting the T helper cell subsets differentiation and antibody secretion mediated by B cells. Reports have shown that E2 promotes Th1 and Treg cell differentiation; whereas it attenuated the Th17 and Tfh cell differentiation. Albeit multiple and contrasting studies, the mechanisms of behind E2 action on Th2 cells remained understudied. Hence, we sought to dissect the impact of E2 in Th2 cell differentiation. In this study, we elucidated the molecular mechanisms behind E2-mediated regulation of the differentiation of Th2 cells. We observed that E2 significantly attenuated the IL-4-secreting Th2 population in an ERα-dependent manner. We validated these findings using ICI 182, 780, an antagonist to ERα, not ERβ and ectopically overexpressing ERα in Th2 cells. We further determined that ERα alters the recruitment of GATA3 and PU.1 to Il4 gene by directly interacting with them. This altered recruitment was observed to be stronger at Il4 than Il13 locus. Interestingly, we detected a distinct recruitment of GATA3 and PU.1 at Il13 gene; however, there was no E2-mediated broad alteration in the recruitment of histone-modifiers at Il13 locus. These findings suggest that E2 regulates Il4 in a distinctly separate mechanism as opposed to Il13 locus in Th2 cells.
17-β 雌二醇（E2）长期以来一直被认为在调节人体生理和免疫系统方面具有重要作用。E2 被认为可以对抗实验性自身免疫性脑脊髓炎（EAE），并已被用作治疗多发性硬化症的药物。此外，E2 通过直接影响 T 辅助细胞亚群的分化和 B 细胞介导的抗体分泌来调节适应性免疫系统。有报道表明，E2 促进 Th1 和 Treg 细胞分化；而减弱 Th17 和 Tfh 细胞分化。尽管有多项相互矛盾的研究，但 E2 对 Th2 细胞作用的机制仍研究不足。因此，我们试图剖析 E2 对 Th2 细胞分化的影响。在这项研究中，我们阐明了 E2 介导的 Th2 细胞分化调节的分子机制。我们观察到，E2 以 ERα 依赖的方式显著减弱了 IL-4 分泌的 Th2 群体。我们使用 ICI 182,780（一种 ERα 拮抗剂，而非 ERβ）和在 Th2 细胞中外源性过表达 ERα 验证了这些发现。我们进一步确定 ERα 通过直接与它们相互作用改变了 GATA3 和 PU.1 向 Il4 基因的募集。这种募集的改变在 Il4 基因上比在 Il13 基因上更强。有趣的是，我们在 Il13 基因上检测到 GATA3 和 PU.1 的明显募集；然而，E2 介导的组蛋白修饰剂在 Il13 基因上的募集没有广泛改变。这些发现表明，E2 在 Th2 细胞中以一种与 Il13 基因明显不同的机制调节 Il4。
