DEXAMETHASONE INHIBITS INDUCTION OF LIVER-TUMOR NECROSIS FACTOR-ALPHAMESSENGER-RNA AND LIVER GROWTH INDUCED BY LEAD NITRATE AND ETHYLENE DIBROMIDE

We have recently demonstrated that a single injection of the mitogen l end nitrate to rats induced a rapid increase of tumor necrosis factor- alpha (TNF-alpha) mRNA in the liver and suggested that this cytokine m ay be involved in triggering hepatocyte proliferation in this model of direct hyperplasia. In this study, we examined whether a similar indu ction of river TNF-alpha mRNA could be observed preceding the onset of hepatocyte proliferation induced by ethylene dibromide, another hepat ocyte mitogen In addition, we used dexamethasone, a well known inhibit or of TNF-alpha production, to determine whether its administration co uld suppress hepatocyte proliferation induced by lead nitrate and ethy lene dibromide. A single intragastric administration of ethylene dibro mide (100 mg/kg) to male Wistar rats enhanced liver TNF-alpha mRNA aft er 4 and 7 hours, which then returned to control levels by 24 hours. T NF-alpha mRNA was detectable only in a nonparenchymal cell fraction of the liver. Pretreatment of rats with a single dose of dexamethasone ( 2 mg/kg) 60 minutes before lead nitrate (100 mu mol/kg) or ethylene di bromide completely abolished the increased levels of liver TNF-alpha m RNA induced by these agents. Inhibition by dexamethasone of TNF-alpha mRNA tons associated with an inhibition of liver cell proliferation in duced by these mitogens, as measured by [H-3]thymidine incorporation i nto hepatic DNA, mitotic index, and DNA content. These results further support the hypothesis that TNF-alpha may be involved in triggering h epatocyte proliferation induced by primary mitogens.