Coexposure to small, noninjurious doses of the pyrrolizidine alkaloid phytotoxin monocrotaline (MCT) and bacterial lipopolysaccharide (LPS) results in synergistic hepatotoxicity. Both centrilobular and midzonal liver lesions occur and are similar to those seen from large, toxic doses of MCT and LPS, respectively. The nature of the lesions in vivo and results from studies in vitro suggest that injury is mediated indirectly rather than from a simple interaction of MCT and LPS with hepatic parenchymal cells. Accordingly, the role of inflammatory factors, such as Kupffer cells and TNF-alpha, in the development of MCT/LPS-induced liver injury was investigated. In Sprague-Dawley rats, MCT (100 mg/kg, i.p.) was administered 4 h before LPS (7.4 x 10(6) EU/kg, i.v.). Pretreatment of these animals with gadolinium chloride, an inhibitor of Kupffer cell function, attenuated liver injury 18 h after MCT administration. An increase in plasma TNF-alpha preceded the onset of hepatic parenchymal cell injury, raising the possibility that this inflammatory cytokine contributes to toxicity. Either pentoxifylline, an inhibitor of cellular TNF-alpha synthesis, or anti-TNF-alpha serum coadministered to MCT/LPS-treated animals significantly attenuated liver injury. These results suggest that Kupffer cells and TNF-alpha are important mediators in the synergistic hepatotoxicity resulting from MCT and LPS coexposure.