Further characterization of Kupffer cell/macrophage-mediated alterations in hepatocyte protein synthesis

Alterations in hepatic function are seen in sepsis or multiple-system organ failure. We have hypothesized that Kupffer cells (KCs) within the liver alter the function of contiguous hepatocytes after exposure to septic stimuli. Using an in vitro coculture system, we have found that lipopolysaccharide (LPS) induced a 40% to 60% decrease in cocultured hepatocyte protein synthesis but had no effect on hepatocytes alone. Coculture in the absence of LPS resulted in enhanced hepatocyte protein synthesis proportional to the number of KCs or macrophages (M0s). Conditioned medium (CM) from LPS-triggered coculture or KC alone decreased protein synthesis of hepatocytes whereas CM from hepatocytes alone had no effect. Gel filtration of active M0-CM showing maximal hepatocyte inhibitory activity was present in fractions between 15,000 and 30,000 daltons. This inhibitory activity was inactivated by exposure to 65 degrees C for 30 minutes. Although CM from untriggered M0 did not inhibit hepatocyte protein synthesis, lysates from both LPS-triggered and control M0 were inhibitory. These results show that M0s/KCs exposed to septic stimuli decrease hepatocyte protein synthesis via heat labile, soluble mediator(s) that may already be synthesized within untriggered cells. We hypothesize that soluble M0/KC mediators normally modulate hepatocyte function and that this normal homeostatic control is profoundly altered during sepsis.