GAMMA-LINOLENIC ACID SUPPRESSION OF HEPATIC ITO CELL MITOGENESIS - POST-PDGF RECEPTOR PROSTAGLANDIN-INDEPENDENT MECHANISM

Ito cell mitogenesis occurs during liver injury and fibrogenesis in vi vo. Platelet-derived-growth factor (PDGF)-induced mitogenesis was stud ied in cultured rat hepatic Ito cells, which resemble the myofibroblas t associated with liver injury. Pretreatment with gamma-linolenic acid (GLA), an essential fatty acid prostanoid precursor, markedly suppres sed the PDGF response in a dose-dependent reversible fashion. Prostagl andins E, and E, were found to be the predominant prostanoids formed b y cultured Ito cells. GLA depressed endogenous PG production, suggesti ng that the antimitogenic effect was independent of GLA conversion to a prostanoid metabolite. The PDGF-induced cascade was studied with and without GLA to determine the level of regulation that induced the obs erved suppression. GLA caused no apparent diminution in the abundance of the surface PDGF-beta receptor nor its subsequent activation and ty rosine phosphorylation after PDGF stimulation. Raf kinase activation a nd Raf perinuclear translocation were also intact despite the presence of GLA. PDGF induction of nuclear Egr and Fos also occurred with or w ithout GLA. Activation of the serine threonine kinase c-Raf has previo usly been found to be sufficient to activate egr and fos and to induce mitogenesis. Therefore, the GLA suppressive effect is likely to be op erative at a parallel non-Raf pathway or distal to Raf-induced early g ene expression.