concanavalin-a and halofuginone

Anti-inflammation strategy is one of the proposed therapeutic approaches to hepatic fibrosis. T helper (Th) 17 cells, which play a detrimental role in experimental murine models of inflammatory diseases, have been demonstrated to participate in the pathogenesis of liver damage. The inhibitory effect of halofuginone (HF), an active component of extracts derived from the plant alkaloid febrifugine, on collagen synthesis has been shown in animal models of the fibrotic disease. The aim of this study was to clarify the in vivo effect of HF on Th17 cells in concanavalin A-induced fibrosis rats. Haematoxylin-eosin (HE) staining and Masson staining were performed to observe collagen deposition. The presence of INF-gamma, TNF-alpha, IL-6, IL-17, IL-1beta, IL-33 and IL-10 in serum and the presence of ROR-γt, IL-17, TGF-β1 and α-SMA in liver tissue were detected. Flow cytometry was performed to analyse the percentage of Th17 cells. We observed significantly lower levels of INF-gamma, TNF-alpha, IL-6, IL-17, IL-1beta, TGF-β1 and α-SMA in HF-treated group of rats, and the percentage of Th17 cells in splenic lymphocyte was decreased well. Histological examination demonstrated that HF significantly reduced the severity of liver fibrosis in HF-treated rats. We concluded that HF (10 mg/kg) exerts an antifibrotic impact on Th17 cells and its relative cytokines in rats with ConA-induced fibrosis.

Topics: Actins; Alanine Transaminase; Albumins; Animals; Aspartate Aminotransferases; Cell Differentiation; Concanavalin A; Disease Models, Animal; Interferon-gamma; Interleukin-10; Interleukin-17; Interleukin-1beta; Interleukin-33; Interleukin-6; Interleukins; Liver; Liver Cirrhosis; Male; Nuclear Receptor Subfamily 1, Group F, Member 3; Piperidines; Protein Synthesis Inhibitors; Quinazolinones; Rats; Rats, Wistar; Th17 Cells; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Halofuginone (HF) is an active component of extracts derived from the plant alkaloid febrifugine and has shown therapeutic promise in animal models of fibrotic disease. Our main objectives were to clarify the suppressive effect of HF on concanavalin A (ConA)-induced liver fibrosis. ConA injection into the tail vein caused a great increase in the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, while orally administration of HF significantly decreased the levels of the transaminases. In addition, the levels of hyaluronic acid (HA), procollagen III (PCIII) and TGF-β1 in the serum and collagen I, α-SMA, tissue inhibitors of metalloproteinase 2 (TIMP2) and Smad3 in the liver tissue were significantly lowered with the treatment of HF. Histological examination also demonstrated that HF significantly reduced the severity of liver fibrosis. Since ConA-induced liver fibrosis is caused by the repeated activation of T cells, immunomodulatory substances might be responsible for the suppressive effect of HF. We found that the production of nuclear factor (NF)-kB in the serum was increased in ConA-treated group, while decreased significantly with the treatment of HF. The changes of inflammatory cytokines tumor necrosis factor (TNF-α), IL-6 and IL-1β in the serum followed the same rhythm. All together, our findings indicate that orally administration HF (10ppm) would attenuate the liver fibrosis by suppressing the synthesis of collagen I and inflammation-mediated liver injury.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Concanavalin A; Drugs, Chinese Herbal; Interleukin-1beta; Interleukin-6; Liver Cirrhosis; Male; Piperidines; Quinazolinones; Rats, Wistar; Transforming Growth Factor beta1