RETINOIC ACID SUPPRESSES THE RESPONSE TO PLATELET-DERIVED GROWTH-FACTOR IN HUMAN HEPATIC ITO-CELL-LIKE MYOFIBROBLASTS - A POSTRECEPTOR MECHANISM INDEPENDENT OF RAF FOS/JUN/EGR ACTIVATION/

Activated Ito-cell-like myofibroblasts proliferate in vivo during huma n liver injury and subsequent fibrogenesis. To examine the associated regulatory mechanisms, human liver myofibroblasts were characterized a fter culture purification from mixed liver-cell isolates obtained from perfused normal human livers. The cells resembled rat Ito-cell-derive d myofibroblasts expressing desmin and alpha-smooth-muscle actin filam ents as well as the interstitial collagens type I and III. [H-3]Thymid ine incorporation was inducible with platelet-derived growth factor (P DGF) and was suppressible with retinoic acid (RAc) in a concentration- dependent fashion. RAc suppression did not alter PDGF alpha- or beta-r eceptor abundance or activation. In addition, RAc functioned via a pat hway distal or independent of cytolasmic raf activation (i.e. phosphor ylation, kinase function and perinuclear translocation) and nuclear fo s, jun and egr expression, as these steps were similarly unaffected by RAc treatment. Since normal Ito cells contain abundant amounts of vit amin A which is lost during activation, these data suggest that retino ids could contribute to the maintenance of the quiescent non-prolifera tive state by suppressing mitogenesis at a post-cytokine receptor step distal from or independent of fos/jun/egr[e.g. via changes in activat or protein-1 (AP-1) binding].