The JAK inhibitor tofacitinib ameliorates immune-mediated liver injury in mice

Abstract

The prevalence of immune-mediated liver diseases such as autoimmune liver disease or viral hepatitis has increased in recent years, and the side effects of pre-existing treatments are a worldwide problem. Regulatory T cells (Tregs) and T helper 17 (Th17) cells play important roles in the development of immune-mediated hepatitis and may serve as potential therapeutic targets. Tofacitinib, a new Janus kinase (JAK) inhibitor, is under investigation for the treatment of rheumatoid arthritis; it is also helpful in treating ulcerative colitis and psoriasis. The roles of tofacitinib were investigated in conferring protection against immune-mediated liver injury in mice. T cell-mediated hepatitis was induced by concanavalin A (ConA). The mice in the treatment groups were administered with tofacitinib intragastrically before the ConA injection. Histopathological examination was performed by hematoxylin and eosin (H&E) staining, and the serum transaminase and inflammatory cytokine levels were determined using an automatic biochemistry analysis apparatus or cytometric bead array (CBA) kits. Flow cytometric analysis was used to detect Tregs and Th17 cells. Tofacitinib significantly decreased the hepatic injury induced by ConA and prominently decreased the liver transaminase level. The secretion of several anti-inflammatory cytokines such as interleukin (IL)-10 was upregulated in mice from the treatment group, compared to that in mice treated with ConA alone, while the expression of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) decreased. Tofacitinib treatment increased the number of Tregs and reduced the number of Th17 cells. Furthermore, tofacitinib could relieve liver fibrosis under conditions of autoimmune hepatitis (AIH). The present results indicated that tofacitinib improved immune-mediated hepatitis and restored the impaired Treg/Th17 cell ratio, which suggests that it may serve as a novel treatment approach for immune-mediated liver diseases.