Suppressive effects of leflunomide on leptin-induced collagen I production involved in hepatic stellate cell proliferation.
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.
Si
H F
HF
Department of Medicine, Anhui Medical University, Hefei 230032, China.
Li
J
J
Lü
X W
XW
Jin
Y
Y
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D003437:Crotonates; D017077:Culture Media, Conditioned / Q000494:pharmacology; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006885:Hydroxybutyrates / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D000077339:Leflunomide; D020738:Leptin / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D009570:Nitriles; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014052:Toluidines
D000814:Aniline Compounds; D024042:Collagen Type I; D003437:Crotonates; D017077:Culture Media, Conditioned; D056741:Cyclin D; D016213:Cyclins; D016207:Cytokines; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D020738:Leptin; D009570:Nitriles; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014052:Toluidines; C527525:teriflunomide; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000077339:Leflunomide