HCV, Acute, LT : Hepatic Stellate Cells Modulate Functions of Tregs in IFNγ-mediated Hepatitis of Mice

Background: Hepatic stellate cells (HSCs) perform important roles not only in liver fibrosis but also in inflammation by regulating activation or induction of immune cells and producing various chemokines and cytokines. Moreover, it has been reported that HSCs are also involved in the induction of regulatory T cells (Tregs). Therefore, we investigated the immune regulatory role of HSCs to Tregs in interferon γ (IFNγ)- mediated hepatitis of mice. Methods: To induce IFNγ-mediated hepatitis in mice, we injected concanavalin A (ConA) to mice through tail vein at dose of 12 μg/g. Mice were sacrificed at 0, 3, 12 and 24 hours after ConA treatment. In vitro experiment, isolated natural Tregs from lymph nodes and spleen were co-cultured with HSCs and then analyzed the FoxP3 expression and gene expressions. Results: After ConA treatment, liver injuries sharply increased a n d p e a k e d a t 2 4 h o u r s a n d t h e p o p u l a t i o n o CD4+CD25+FoxP3+ Tregs was also significantly increased. In addition, isolated HSCs after ConA treatment showed enhanced expressions of TGF-β and IL-10. In vitro co-culturing Tregs with HSCs, HSCs significantly up-regulated Foxp3 expression in Tregs compared to that of non-co-cultured Tregs. Moreover, levels of IL-10 and TGF-β at supernatant remarkably increased in the co-cultured group compared with those of Tregs or HSCs only cultured group. Conclusions: In ConA-induced hepatitis, HSCs might regulate the expression of FoxP3 in Tregs by producing cytokines such as IL-10 and TGF-β. Therefore, the regulation of function in HSCs could be a new therapeutic target for immune-mediated hepatitis.