Modulation of hepatocyte protein synthesis by endotoxin-activated Kupffer cells. II. Mediation by soluble...

We have previously reported a diminution of protein synthesis by isolated Sprague-Dawley rat hepatocytes following coculture with lipopolysaccharide-triggered nonparenchymal liver cells (NPC) containing 30-40% Kupffer cells. It is possible that this cell-mediated modulation of hepatocyte function represents an in vitro model for hepatic insufficiency occurring in patients with the multiple system organ failure syndrome. In the present report we have determined that supernatant from lipopolysaccharide-triggered NPC was itself capable of inhibiting hepatocyte protein synthesis in a similar fashion. This effect was directly related to the concentration of the supernatant and to the period of exposure to the supernatant. The ability to inhibit hepatocyte protein synthesis by a NPC supernatant suggests that this cell-mediated event is caused at least in part by a relatively stable soluble factor(s) secreted by LPS triggered NPC. Although reagent H2O2 will inhibit protein synthesis when added to hepatocyte culture, LPS-stimulated NPC do not release H2O2 and do not show chemiluminescence--an in vitro correlate of the respiratory burst. Nonspecific protease inhibitors added to the coculture similarly do not influence the system. Combined with other evidence, the soluble mediators do not seem to be the result of oxidative or proteolytic secretions of the effector cells.