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Stimulation of cell proliferation caused by peroxisome proliferators was blocked by antibodies against TNFα and agents that inactivate Kupffer cells, a rich source of TNFα, which supports the hypothesis that Kupffer cells play a pivotal role in peroxisome proliferator-induced hyperplasia. Here, the ability of the very potent peroxisome proliferator WY-14 643 to activate the transcription factor NF-κB in rat liver was examined since it is involved in TNFα production. Female Sprague-Dawley rats were treated by gavage with WY-14 643 (100 mg/kg) while control animals were given equivalent doses of vehicle (olive oil). Activation of NF-κB in both whole liver, non-parenchymal cells, Kupffer cells and hepatocytes was assessed for up to 36 h using an electrophoretic mobility shift assay. In whole liver, WY-14 643 transiently increased NF-κB binding maximally 3.5-fold in 2-8 h followed by a steady decline to near control levels at 36 h. As early as 2 h after WY-14 643 treatment, the active form of NF-κB was localized predominantly in Kupffer cells with values 20- to 25-times greater than in hepatocytes. In hepatocytes, a small increase in NF-κB binding was observed but only 8 h after WY-14 643 administration. Pre-treatment with allopurinol, a xanthine oxidase inhibitor and free radical scavenger, suppressed NF-κB activation by WY-14 643 almost completely. It is concluded that NF-κB is activated by reactive oxygen species and plays a central role in the mechanism of action of peroxisome proliferators. Moreover, these findings support the hypothesis that Kupffer cells play a pivotal role in peroxisome proliferator-induced hepatocyte proliferation through rapid NF-κB activation and subsequent induction of TNFα production. TNFα from Kupffer cells stimulates growth in parenchymal cells later via mechanisms that also involve NF-κB. [ABSTRACT FROM PUBLISHER]