Suppressive effect of leflunomide on rat hepatic stellate cell proliferation involves on PDGF-BB-elicited activation of three mitogen-activated protein kinases.
In this manuscript, we demonstrated that following stimulus by Kupffer cell-conditioned medium (KCM) and PDGF-BB, hepatic stellate cells (HSCs) showed significant increases in DNA synthesis and PDGFR-beta expression. Furthermore, phosphorylation of PDGFR-beta and three major members of the mitogen-activated protein kinase (MAPK) family were also significantly increased. Studies with respective neutralizing antibodies against released cytokines in conditioned medium demonstrated that PDGF-BB played an essential role in this complex activation process. Administration of A771726, leflunomide's metabolite, markedly blunted these effects. However, the combination of A771726 with any of the three MAPK inhibitors potentiated this inhibitory effect and showed completely blockage on PDGFR-beta expression and phosphorylation. Collectively, these data demonstrate that leflunomide inhibits KCM-mediated HSC proliferation via PDGFR-beta phosphorylation and the subsequent activation of the MAPK pathway. Accordingly, targeted intervention against the PDGF-BB isoform may also offer a promising therapeutic approach to liver fibrosis.
Si
H F
HF
School of Pharmacy, Anhui Medical University, Hefei 230032, China.
Lv
Xiongwen
X
Guo
Anping
A
Jiang
Hui
H
Li
Jun
J
D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003437:Crotonates; D017077:Culture Media, Conditioned; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D006885:Hydroxybutyrates / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000378:metabolism; D007555:Isoxazoles / Q000378:metabolism / Q000494:pharmacology*; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism; D000077339:Leflunomide; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014052:Toluidines
D000814:Aniline Compounds; D003437:Crotonates; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D014052:Toluidines; D000077214:Becaplermin; C527525:teriflunomide; D020797:Receptor, Platelet-Derived Growth Factor beta; D020928:Mitogen-Activated Protein Kinases; D000077339:Leflunomide