Evidence that activation of Kupffer cells results in production of l-arginine metabolites that release cell-associated iron and inhibit hepatocyte protein synthesis

Activated macrophages are known to metabolize l-arginine to unstable intermediates that induce cytotoxic activity through the release of mitochondrial iron in target cells. We have recently shown that rat Kupffer cells (KC) use l-arginine to inhibit cocultured hepatocyte (HC) protein synthesis. Based on these two facts, a hypothesis is proposed that endotoxin-triggered KC release intermediates of l-arginine metabolism that inhibit HC protein synthesis by oxidizing iron at critical mitochondrial enzymes, thus interfering with mitochondrial respiration and energy production. Results of experiments testing this hypothesis showed that the metabolism of l-arginine was required for inhibition of protein synthesis and iron release and that the end products of l-arginine metabolism did not possess cytostatic or cytotoxic activity toward HC. The possibility that this cell culture phenomenon might provide insights into the mechanism of hepatic insufficiency in sepsis is raised.