Retinoic acid suppresses the response to platelet-derived growth factor in human hepatic Ito-cell-like myofibroblasts: a post-receptor mechanism independent of raf/fos/jun/egr activation.
Activated Ito-cell-like myofibroblasts proliferate in vivo during human liver injury and subsequent fibrogenesis. To examine the associated regulatory mechanisms, human liver myofibroblasts were characterized after culture purification from mixed liver-cell isolates obtained from perfused normal human livers. The cells resembled rat Ito-cell-derived myofibroblasts expressing desmin and alpha-smooth-muscle actin filaments as well as the interstitial collagens type I and III. [3H]Thymidine incorporation was inducible with platelet-derived growth factor (PDGF) and was suppressible with retinoic acid (RAc) in a concentration-dependent fashion. RAc suppression did not alter PDGF alpha- or beta-receptor abundance or activation. In addition, RAc functioned via a pathway distal or independent of cytoplasmic raf activation (i.e. phosphorylation, kinase function and perinuclear translocation) and nuclear fos, jun and egr expression, as these steps were similarly unaffected by RAc treatment. Since normal Ito cells contain abundant amounts of vitamin A which is lost during activation, these data suggest that retinoids could contribute to the maintenance of the quiescent non-proliferative state by suppressing mitogenesis at a post-cytokine receptor step distal from or independent of fos/jun/egr [e.g. via changes in activator protein-1 (AP-1) binding].
Davis
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Department of Medicine, University of Chicago, IL 60637.
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D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology*; D008103:Liver Cirrhosis / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014212:Tretinoin; D017479:Receptors, Platelet-Derived Growth Factor; D019908:Proto-Oncogene Proteins c-raf