Pregnenolone sulfate induces transcriptional and immunoregulatory effects on T cells.

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.

Hyperglycemic conditions induce rapid cell dysfunction-promoting transcriptional alterations in human aortic endothelial cells.

Hyperglycemia is a major risk factor in the development of diabetic complications and promotes vascular complications through dysregulation of endothelial cell function. Various mechanisms have been proposed for endothelial cell dysregulation but the early transcriptomic alterations of endothelial cells under hyperglycemic conditions are not well documented. Here we use deep time-series RNA-seq profiling of human aortic endothelial cells (HAECs) following exposure to normal (NG) and high glucose (HG) conditions over a time course from baseline to 24 h to identify the early and transient transcriptomic changes, alteration of molecular networks, and their temporal dynamics. The analysis revealed that the most significant pathway activation/inhibition events take place in the 1- to 4-h transition and identified distinct clusters of genes that underlie a cascade of coordinated transcriptional events unique to HG conditions. Temporal co-expression and causal network analysis implicate the activation of type 2 diabetes (T2D) and growth factor signalling pathways including STAT3 and NF-κB. These results document HAEC transcriptional changes induced by hyperglycemic conditions and provide basic insight into the rapid molecular alterations that promote endothelial cell dysfunction.