Extracellular signal-regulated kinase activation differentially regulates platelet-derived growth factor's actions in hepatic stellate cells, and is induced by in vivo liver injury in the rat

Upon liver injury, hepatic stellate cells (HSC) show increased proliferatio n, motility, and extracellular matrix (ECM) production. The extracellular s ignal-regulated kinases (ERK) control different functions in a cell-specifi c manner. In this study, we evaluated the role of ERK activation in culture d HSC stimulated with platelet-derived growth factor (PDGF) and after induc tion of liver injury in vivo. HSC were isolated from normal human liver tis sue, cultured on plastic, and used in their myofibroblast-like phenotype. I n in vivo experiments, HSC were isolated from normal rats or at different t ime points after a single intragastric administration of CCl4. Nontoxic con centrations of PD98059, a specific inhibitor of ERK activation, reduced PDG F-induced activation of ERK in a dose-dependent fashion. Suppression of ERK activation was associated with complete inhibition of HSC proliferation an d with a 57% reduction in chemotaxis. In the presence of the ERK inhibitor, binding of the AP-1 complex and of STAT1 to the related regulatory element s was inhibited. The inhibition of the DNA binding activity of STAT1 was me diated by a reduction in PDGF-induced tyrosine phosphorylation. Expression of c-fos in response to PDGF was also reduced, but not suppressed, by treat ment with PD98059. In HSC isolated from CCl4-treated rats, ERK activity inc reased as early as 6 hours following liver damage, and declined thereafter. The results of this study indicate that ERK activation regulates prolifera tion and chemotaxis of HSC, and modulates nuclear signaling. Acute liver da mage in vivo leads to activation of ERK in HSC.