The JAK inhibitor tofacitinib ameliorates immunemediated liver injury in mice.
Mol Med Rep
; 20(6): 4883-4892, 2019 Dec.
Article
en En
| MEDLINE
| ID: mdl-31638166
ABSTRACT
The prevalence of immunemediated liver diseases such as autoimmune liver disease or viral hepatitis has increased in recent years, and the side effects of preexisting treatments are a worldwide problem. Regulatory T cells (Tregs) and T helper 17 (Th17) cells play important roles in the development of immunemediated 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 immunemediated liver injury in mice. T cellmediated 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 antiinflammatory 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 interferonγ (IFNγ) and tumor necrosis factorα (TNFα) 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 immunemediated hepatitis and restored the impaired Treg/Th17 cell ratio, which suggests that it may serve as a novel treatment approach for immunemediated liver diseases.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperidinas
/
Pirimidinas
/
Pirroles
/
Hepatitis Autoinmune
/
Inhibidores de las Cinasas Janus
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Mol Med Rep
Año:
2019
Tipo del documento:
Article