PROSTAGLANDIN-E SUPPRESSION OF PLATELET-DERIVED-GROWTH-FACTOR-INDUCEDITO CELL MITOGENESIS OCCURS INDEPENDENT OF RAF PERINUCLEAR TRANSLOCATION AND NUCLEAR PROTOONCOGENE EXPRESSION

Ito cell mitogenesis occurs during liver injury and fibrogenesis in vi vo coincident with the de novo expression of Ito cell PDGF beta recept or messenger RNA, PDGF-induced mitogenesis was studied in cultured rat hepatic Ito cells which resemble the myofibroblast associated with li ver injury. Pretreatment with prostaglandin E markedly suppressed the PDGF response in a dose-dependent fashion. The PDGF-induced cascade wa s studied with or without PGE to determine the level of regulation whi ch induced the observed suppression. PGE caused no apparent diminution in the abundance of the surface PDGF beta receptor nor its subsequent activation and tyrosine phosphorylation following PDGF stimulation. T he cytoplasmic 'secondary messengers' mitogen-activated protein kinase pp42-44 and raf kinase, appeared to be comparably induced and therefo re unaffected by PGE. Raf perinuclear translocation was also intact an d comparable degrees of nuclear egr, fos, and jun expression occurred. Since other studies have suggested that many of these features of the PDGF cascade may be causally and sequentially linked, the data collec tively suggests that the dominant PGE mitogenic suppressive effect res ides at a raf-MAP parallel pathway or at a nuclear level distal to the induction of these early growth response genes.