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.

Regulatory T Cells in Autoimmune Hepatitis: Unveiling Their Roles in Mouse Models and Patients

“…Some other studies have also provided evidence for the curative effect of Tregs adoptive transfer in different AIH mouse models ( 82 , 86 , 91 ). Several animal studies have investigated improving the Tregs frequency ( 88 ) or the impaired Treg/Th17 balance ( 83 , 85 , 92 ) in the liver to reduce immune-mediated liver damage in mice. In general, owing to the different mechanisms in the different mouse models to trigger AIH, it is reasonable to have incoherent observation results from various studies.…”

Novel Immune Subsets and Related Cytokines: Emerging Players in the Progression of Liver Fibrosis

“…Mesenchymal stem cells have also been reported to restrict liver fibrosis by inhibiting Th17 cells ( 115 , 116 ). In addition, miR-29a/miR-652, 1, 25(OH)2D3, as well as certain drugs, such as rapamycin and tofacitinib, have been shown to attenuate liver fibrosis by regulating Th17 cells ( 10 , 11 , 117 , 118 ). Meanwhile, low dose IL-2 specifically expands and activates Treg cell populations thereby controlling autoimmune diseases and inflammation.…”

“…For instance, an imbalance in the ratio of regulatory T cells (Tregs)/T helper 17 cells (Th17) is characteristic of liver fibrosis progression. Indeed, some drugs function to restore the Tregs/Th17 balance, thereby alleviated liver fibrosis ( 7 – 11 ). Additionally, Th22, Th9, mucosa-associated invariant T (MAIT) cells, innate lymphoid cells (ILCs), γδ T cells, and their related cytokines, have been reported to regulate liver fibrosis ( 12 – 16 ).…”

Combined anti-fibrotic and anti-inflammatory properties of JAK-inhibitors on macrophages in vitro and in vivo: Perspectives for scleroderma-associated interstitial lung disease

“…These effects of tofacitinib and baricitinib in rheumatoid arthritis are especially mediated through their impact on the plasma levels of pro-inflammatory cytokines such as IL-6 and IL-17, that play an important role in the immune-mediated inflammatory manifestations of this autoimmune connective tissue disease (6,7). Beyond these anti-inflammatory effects, JAK inhibitors could also exert anti-fibrotic properties (8), possibly due to their direct impact on fibroblast activation (9), in various fibrotic disorders, such as autoimmune liver fibrosis or idiopathic pulmonary fibrosis (8,10,11). Nonetheless, the precise cellular targets of JAK inhibitors are still to be further explored, specifically in the context of fibrotic and autoimmune diseases (12).…”