Davis B H, Coll D, Beno D W
Department of Medicine, University of Chicago, IL 60637.
Biochem J. 1993 Sep 15;294 ( Pt 3)(Pt 3):785-91. doi: 10.1042/bj2940785.
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].
活化的类肝星状细胞样肌成纤维细胞在人类肝损伤及随后的纤维化过程中在体内增殖。为了研究相关的调控机制，从灌注正常人类肝脏获得的混合肝细胞分离物中进行培养纯化后，对人类肝脏肌成纤维细胞进行了特性分析。这些细胞类似于大鼠肝星状细胞衍生的肌成纤维细胞，表达结蛋白和α-平滑肌肌动蛋白丝以及I型和III型间质胶原。[3H]胸苷掺入可被血小板衍生生长因子（PDGF）诱导，并可被视黄酸（RAc）以浓度依赖的方式抑制。RAc抑制并未改变PDGFα或β受体的丰度或激活。此外，RAc通过一条远离或独立于细胞质raf激活（即磷酸化、激酶功能和核周转位）以及核fos、jun和egr表达的途径发挥作用，因为这些步骤同样不受RAc处理的影响。由于正常肝星状细胞含有大量在激活过程中丢失的维生素A，这些数据表明类视黄醇可能通过在细胞因子受体后一步抑制有丝分裂，在远离或独立于fos/jun/egr的步骤（例如通过激活蛋白-1（AP-1）结合的变化）来维持静止的非增殖状态。
