Peptide mediators, including tumor necrosis factor-a, interleukin 1 and interleukin-6, are associated with many chronic inflammatory diseases and septic shock. As such, considerable information has been collected by means of study of cytokine secretion from isolated cells or plasma cytokines during septic shock or idammatory disorders. In this investigation, we used semiquantitative polymerase chain reaction analysis and a recently developed liver slice model to examine the characteristics of cytokine profiles that occur in the liver, the main organ involved in endotoxemia, after lipopolysaccharide challenge. Tumor necrosis factor-a, interleukinla and interleukin-6 were rapidly secreted after in uiuo LPS exposure or when added in vitro to rodent or human liver slice samples. This increase was associated with increased cytokine-specific mRNA transcripts. Kinetic analysis revealed that most tumor necrosis factor-a is released from the liver within 1 hr of lipopolysaccharide challenge, whereas interleukin-la and interleukin-6 continued to be produced for the entire culture period. Addition of monoclonal antibodies against tumor necrosis factor-a or interleukin-la to the culture partly inhibited interleukin-6 secretion, indicating that interleukin-la and tumor necrosis factor-a help mediate and sustain interleukin-6 synthesis. Depletion of hepatic sinusoidal macrophages (Kupffer cells) by a liposome-mediated macrophage "suicide" technique indicated that almost all of the secreted interleukinla and tumor necrosis factor-a originate from these cells, whereas interleukin-6 secretion might also include other cell types. This study supports and extends previous findings and allows for a more rational approach to developing effective therapies against chronic inflammatory diseases and septic shock. (HEPATOLOGY 1994; 19:480-488.) Gram-negative bacterial endotoxins (i.e., lipopolysaccharide [LPS]) are associated with tissue injury and fatal