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ORIGINAL RESEARCH ARTICLE

Suppressive Effects of Leflunomide on Leptin-Induced Collagen I Production Involved in Hepatic Stellate Cell Proliferation

Department of Medicine, Anhui Medical University, Hefei 230032, China

To whom requests for reprints should be addressed at ¹ Department of Medicine, Anhui Medical University, Hefei 230032, China. E-mail: lijun{at}ahmu.edu.cn

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 [³H]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.

Key Words: leptin • hepatic stellate cells • proliferation • signal pathways • Kupffer cells • leflunomide • liver fibrosis

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