leptin and teriflunomide

This manuscript revealed that following a fibrogenic stimulus of leptin in vitro, hepatic stellate cells (HSCs) underwent a complex activation process characterized by increased proliferation and excessive tissue inhibitor of metalloproteinase-1 (TIMP-1) production. Studies with special chemical inhibitors demonstrated that this process involved Janus protein tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinases (MAPK), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal pathways. Pretreatment with A771726 (alpha,alpha,alpha-Trifluoro-5-methyl-4-isoxazolecarboxy-p-toluidide), leflunomide's metabolite, fully prevented leptin-induced TIMP-1 production in HSCs. This effect was associated with its suppression on HSC proliferation and induction of HSC apoptosis.

Topics: Aniline Compounds; Animals; Apoptosis; Cell Proliferation; Cells, Cultured; Crotonates; Hydroxybutyrates; Immunosuppressive Agents; Isoxazoles; Janus Kinases; Leflunomide; Leptin; Liver; Mitogen-Activated Protein Kinases; Nitriles; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; STAT Transcription Factors; Tissue Inhibitor of Metalloproteinase-1; Toluidines

In this manuscript, we showed that following a fibrogenic stimulus of leptin, hepatic stellate cells (HSCs) underwent a complex activation process characterized by increased proliferation and excessive deposition of type I collagen. Studies with special chemical inhibitors demonstrated that this process involved Janus protein tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinases (MAPK), and phosphatidylinositol 3-linase (PI3K)/Protein kinase B (AKT) signal pathways. Leflunomide pretreatment significantly inhibited the deposition of type I collagen in HSCs and the proliferation of primary HSC by interrupting the three proliferative signal transduction pathways in vitro, which was indicated by [(3)H]thymidine incorporation and cell cycle analysis. Furthermore, leptin-induced cyclin D1 protein expression, which correlates well with HSC proliferation, was also significantly inhibited by leflunomide. On the other hand, leflunomide also prevented leptin-induced Kupffer cell (KC) activation and HSC collagen synthesis induced by KC-conditioned medium (KCCM). Collectively, these results provided a novel insight into the mechanisms by which leflunomide may exert in liver fibrosis.

Topics: Aniline Compounds; Animals; Cell Cycle; Cell Proliferation; Cells, Cultured; Collagen Type I; Crotonates; Culture Media, Conditioned; Cyclin D; Cyclins; Cytokines; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Hydroxybutyrates; Immunosuppressive Agents; Isoxazoles; Kupffer Cells; Leflunomide; Leptin; Liver; Macrophage Activation; Nitriles; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Toluidines