The lncRNA HOTAIR via miR-17-5p is involved in arsenite-induced hepatic fibrosis through regulation of Th17 cell differentiation.

Abstract

Arsenic compounds are toxins that are widely distributed in the environment. Chronic exposure to low levels of these compounds can cause hepatic fibrosis and other damage. Th17 differentiation of CD4+ T cells and the secretion of IL-17 activates hepatic stellate cells (HSCs), which are involved in hepatic fibrosis, but their mechanisms in arsenic-induced hepatic fibrosis are unclear. We found, in arsenite-induced fibrotic livers of mice, increases of CD4+ T cell infiltration, Th17 cell nuclear receptor retinoic acid receptor-related orphan receptor γt (RORγt), and secretion of the pro-inflammatory cytokine IL-17. There were also elevated levels of the lncRNA, HOTAIR. For Jurkat cells, arsenite elevated levels of HOTAIR and protein levels of RORγt and IL-17A, decreased miR-17-5p, promoted Th17 cell differentiation, and released IL-17. The culture medium of arsenite-treated Jurkat cells activated LX-2 cells. Down-regulation of HOTAIR or up-regulation of miR-17-5p blocked arsenite-induced Th17 cell differentiation, which inhibited the LX-2 cell activation. However, down-regulation of HOTAIR and miR-17-5p reversed this inhibitory effect. For mice, silencing of HOTAIR diminished the hepatic levels of RORγt and IL-17A and alleviated arsenite-induced hepatic fibrosis. These results demonstrate that, for CD4+ T cells, arsenite promotes RORγt-mediated Th17 cell differentiation through HOTAIR down-regulation of miR-17-5p, and increases the secretion of cytokine IL-17A, which activates HSCs; the activated HSCs facilitate hepatic fibrosis. The findings reveal a new mechanism and a potential therapeutic target for arsenite-induced hepatic fibrosis.