Multiple Cytokines Are Required to Induce Hepatocyte Nitric Oxide Production and Inhibit Total Protein Synthesis

Abstract

The etiology and mechanisms by which severe trauma or sepsis induce hepatic failure are unknown. Previously we showed that Kupffer cells (KC), the fixed macrophages of the liver, induce a profound decrease in hepatocyte (HC) total-protein synthesis when exposed to endotoxin. Furthermore we demonstrated that endotoxin-activated KCs induce these changes in HC protein synthesis through the induction of a novel L-arginine-dependent biochemical pathway within the HC. In this pathway, the guanido nitrogen of L-arginine is converted to the highly reactive molecule nitric oxide (NO.). To identify the KC factors that act as signals for induction of HC NO. biosynthesis, recombinant cytokines were added to HC cultures and HC nitrogen oxide production and protein synthesis levels were determined. We found that no single cytokine, but rather a specific combination of tumor necrosis factor, interleukin-1, interferon-gamma, and endotoxin, were required for maximal induction of HC nitrogen oxide production. This specific combination of cytokines induced a 248.8 +/- 26.0 mumol/L (micromolar) increase in HC nitrogen oxide production and simultaneously inhibited HC total protein synthesis by 36.1% +/- 3.1%. These data demonstrate that multiple cytokines, produced by endotoxin-activated KC, induce the production of NO. within HC, which in turn leads to the inhibition of HC total-protein synthesis.

Nitric oxide in liver injury

“…Although it was first identified in macrophages induced as part of an inflammatory response, 10 iNOS has been identified also in endothelial cells, 11,12 hepatocytes, 13,14 and hepatic stellate cells 15,16 as well as cholangiocytes. Unlike eNOS, which produces relatively small levels of NO and has a very fast time constant for activation and inactivation (seconds), iNOS produces much larger quantities of NO.…”

The anti-inflammatory drug sodium salicylate inhibits nitric oxide formation induced by interleukin-1? at a translational step, but not at a transcriptional step, in hepatocytes

“…6,[8][9][10][11][12] Thus such The objective of this study was to investigate an ability a combination of cytokines and LPS is routinely used for of the anti-inflammatory drug NaSA to affect the producexperiments of iNOS induction by most of investigators. Howtion of NO in hepatocytes.…”

In vivoregulation of inducible NO synthase in immune-mediated liver injury in mice

“…TNF and IFN-␥ have been shown to be strong inducers of iNOS expression in vitro. [10][11][12] iNOS, as the inducible member of the 3 NO synthase isoforms, 13 catalyzes the oxidationreduction reaction of L-arginine in the presence of oxygen to form the free radical NO and L-citrulline. Under normal conditions, only the constitutive endothelial NOS is present in the liver and low levels of NO regulate the hepatic perfusion.…”