The authors previously reported that unstimulated peritoneal macrophages and LPS stimulated Kupffer cell-rich nonparenchymal liver cells (NPC) can inhibit protein synthesis in cultured rat hepatocytes. Hepatocyte function was similarly altered by supernatants from LPS-triggered NPC. Secretory products of macrophages and Kupffer cells (monokines) are possible mediators in this model of cell-mediated modulation of hepatocyte function. In this article, supernatants from NPC capable of altering hepatocyte protein synthesis were found to contain significant amounts of one monokine, interleukin-1 (IL-1). The kinetics of the generation of the ability to inhibit protein synthesis and the appearance of IL-1 activity were roughly parallel for the first 24 hours. Exposure of hepatocytes to NPC supernatant and commercially available highly purified IL-1 resulted in similar response patterns with regard to onset of inhibition and progression of suppression after removal. Certain discrepancies cast doubt, however, on the likelihood that IL-1 is the mediator in this model of cell-mediated inhibition of hepatocyte protein synthesis. Commercial human IL-1 preparations did not always suppress protein synthesis in cultured rat hepatocytes. Furthermore, IL-1 activity was stable for several days but hepatocyte inhibition was lost. Unstimulated peritoneal macrophage supernatants containing IL-1 activity could not inhibit protein synthesis in hepatocytes. The evidence supports the idea that appropriately stimulated cells of monocyte-macrophage lineage (including Kupffer cells that lie in direct apposition to hepatocytes) could mediate hepatocyte malfunction by means of secreted monokines similar to, but not necessarily identical to, IL-1.