Program in Biology, Division of Science and Mathematics, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
Core Technology Platforms, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
Sci Rep. 2024 Mar 21;14(1):6782. doi: 10.1038/s41598-024-57327-0.
Pregnenolone sulfate is a steroid metabolite of the steroidogenesis precursor, pregnenolone, with similar functional properties, including immunosuppression. We recently reported an elevation in serum levels of pregnenolone sulfate in children with malaria, contributing to an immunosuppressed state. Yet, the molecular mechanisms in which this steroid exerts its immunoregulatory functions are lacking. In this study, we examined the effects of pregnenolone sulfate on T cell viability, proliferation and transcriptome. We observed a pregnenolone sulfate dose-dependent induction of T cell death and reduction in proliferation. RNA sequencing analysis of pregnenolone sulfate-treated T cells for 2 and 24 h revealed the downregulation of pro-inflammatory genes and the upregulation of the steroid nuclear receptor superfamily, NR4A, as early-response genes. We also report a strong activation of the integrated stress response mediated by the upregulation of EIF2AK3. These results contribute to the knowledge on transcriptional regulation driving the immunoregulatory effects of pregnenolone sulfate on T cells.
硫酸孕烯醇酮是甾体激素生物合成前体孕烯醇酮的代谢产物，具有相似的功能特性，包括免疫抑制作用。我们最近报道，疟疾患儿血清硫酸孕烯醇酮水平升高，导致免疫抑制状态。然而，这种甾体激素发挥免疫调节功能的分子机制尚不清楚。在这项研究中，我们研究了硫酸孕烯醇酮对 T 细胞活力、增殖和转录组的影响。我们观察到硫酸孕烯醇酮剂量依赖性诱导 T 细胞死亡和增殖减少。硫酸孕烯醇酮处理的 T 细胞在 2 小时和 24 小时的 RNA 测序分析显示，促炎基因下调，类固醇核受体超家族 NR4A 作为早期反应基因上调。我们还报告了由 EIF2AK3 上调介导的整合应激反应的强烈激活。这些结果有助于了解转录调控驱动硫酸孕烯醇酮对 T 细胞的免疫调节作用。
