Suppressive effects of leflunomide on leptin-induced TIMP-1 production involves on hepatic stellate cell proliferation and apoptosis

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.