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Experimental Biology and Medicine 232:427-436 (2007)
© 2007 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

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

H. F. Si, J. Li1, X. W. Lü and Y. Jin

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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Copyright © 2007 by the Society for Experimental Biology and Medicine.