Lead nitrate induces liver cell proliferation in rats without accompanying liver cell necrosis. However, the mechanism of this proliferation and its effect on hepatocytes remain unknown. Therefore, we examined the liver and blood level of hepatocyte growth factor and tumor necrosis factor alpha (TNF-alpha) at various intervals to determine whether lead nitrate modifies hepatocyte proliferation by altering the production of these cytokines. We also administered several TNF-alpha inhibitors, dexamethasone, adenosine, (2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonyl-2- propenoic acid (E 3330), and pentoxifylline, to rats to clarify whether pretreatment with these inhibitors suppresses the increase of TNF-alpha messenger RNA (mRNA) in the liver and prevents the hepatocyte proliferation induced by lead nitrate. Hepatocyte proliferation occurred by 24 hours and reached a peak 48 hours after a single intravenous injection of lead nitrate (100 mumol/kg). TNF-alpha mRNA expression in the liver was increased 1, 6, and 12 hours after the injection, whereas no alteration was observed in liver or blood level of hepatocyte growth factor. Pretreatment with dexamethasone (4.0 mg/kg), E3330 (100 mg/kg) adenosine (0.3 mmol/kg), and pentoxifylline (100 mg/kg), inhibited both TNF-alpha mRNA expression and hepatocyte proliferation 48 hours after the injection. These experimental results strongly support the hypothesis that TNF-alpha positively regulates the hepatocyte proliferation induced in rats by the mitogen, lead nitrate.