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.
School of Pharmacy, Anhui Medical University, Heifei, 230032, Anhui Province, China. lijun@ahmu.edu.cn
Jun
J
Li
H F
HF
Si
Xiongwen
X
Lü
Anping
A
Guo
Hui
H
Jiang
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003437:Crotonates; D006885:Hydroxybutyrates / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D053612:Janus Kinases / Q000187:drug effects / Q000378:metabolism; D000077339:Leflunomide; D020738:Leptin / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D050791:STAT Transcription Factors / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects* / Q000378:metabolism; D014052:Toluidines
D000814:Aniline Compounds; D003437:Crotonates; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D053612:Janus Kinases; D000077339:Leflunomide; D020738:Leptin; D020928:Mitogen-Activated Protein Kinases; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D050791:STAT Transcription Factors; D019715:Tissue Inhibitor of Metalloproteinase-1; D014052:Toluidines; C527525:teriflunomide