DIFFERENTIAL MODULATION OF HEPATOCYTE GROWTH FACTOR-STIMULATED MOTILITY BY TRANSFORMING-GROWTH-FACTOR BETA-1 ON RAT-LIVER EPITHELIAL-CELLS IN-VITRO

We have previously shown that transforming growth factor-beta 1 (TGF-b eta 1) enhances the epidermal growth factor-(EGF) and transforming gro wth factor-alpha (TGF-alpha)-stimulated motility of rat hepatocytes in an extracellular matrix (ECM)-dependent fashion (Stolz and Michalopou los, 1997, J. Cell. Physiol., 170:57-68). We have extended th is study to examine the effects of TGF-beta 1 on hepatocyte growth factor (HGF ) and EGF-stimulated motility of rat nonparenchymal liver epithelial c ells (RLECs) in vitro and determined that chemotaxis, scattering, and monolayer wound healing by EGF was synergistically enhanced by TGF-bet a 1 on all ECMs examined. However, HGF-based motility, unlike EGF-stim ulated motility, was modulated in an assay-dependent manner by TGF-bet a 1. HGF-stimulated chemotaxis was dramatically decreased by addition of TGF-beta 1, but wound healing was synergistically enhanced by TGF-b eta 1 on all ECMs examined. HGF-based scattering was not consistently affected by TGF-beta 1 on any ECM tested except on laminin, where scat tering was often reduced by the concomitant addition of TGF-beta 1. TG F-beta 1 enhanced the motility associated with monolayer wound healing by HGF or EGF independent of DNA synthesis, because tritiated thymidi ne uptake was consistently reduced by 60% in the presence of TGF-beta 1. The data indicate that HGF and EGF motility do not follow redundant signal-transduction pathways and that specific growth factor motility -related events, as measured by wound healing, scattering, and chemota xis, are modulated independently by ECM and TGF-beta 1. (C) 1998 Wiley -Liss, Inc.