TNF-a but not IL-1a: DISCUSSION
D-GalN administration is a model of hepatotoxicity used extensively in experimental studies. D-GalN depletes the intra- cellular uracil nucleotides in hepatocytes that lead to inhibition of RNA and protein synthesis. D-GalN increases serum transaminase levels, hepatic necrosis and coma. In the present study and in another, D-GalN induced liver injury and increased TNF-a concentration in rat serum. TNF-a is essential to induce cell death in unviable hepatocytes and exacerbates D-GalN-induced damage. In this sense, TNF-a treatment induces apoptosis in vivo and in vitro when D-GalN is also administered. Under our conditions, a short time after D-GalN portal infusion, a significant increase in serum ALT (Figure 1) and TNF-a (Figure 2) was observed compared with the control group. Nevertheless, the serum concentrations of IL-1a (Figure 3) and NOx (Figure 4) did not change with D-GalN administration. Such inability of D-GalN to stimulate IL-1 a release has also been pointed out using IL-1 receptor antagonist to prevent the lethal combination of TNF-a and D-GalN treatment. Because the manufacturer indicated that the D-GalN had no trace amount of endotoxin, our results indicate that D-GalN is able to stimulate inflammatory cells to release inflammatory mediators. In our experimental conditions, the toxicity induced by D-GalN was low, and ALT levels (Figure 1) decreased 15 mins after infusion. This may be due to the low dose of D-GalN used or some other extrahepatic changes induced by D-GalN.
Several reports have shown that PGE1 decreases both in vivo and in vitro the liver damage induced by D-GalN. In a previous study, intraperitoneal preadministration of PGE1 30 mins before D-GalN reduced ALT release and enhanced TNF-a concentration in serum. In the present study, protection by PGE1 against D-GalN was also obtained when PGE1 was infused 10 mins before D-GalN through the portal vein, indicating that the different effects may be restricted to the liver and/or systemic circulation. Such stimulation of TNF-a release induced by PGE1 differs from the results of some other experiments. In these studies, it has been observed that PGE reduces TNF-a release in vitro from LPS-stimulated Kupffer cells and peritoneal macrophages. The authors pointed out that this effect of PGE1 was related to cAMP formation. Nevertheless, in agreement with our data, other authors have reported that low PGE concentration stimulates cGMP and TNF-a release from peritoneal macrophages. In vivo experiments have also given controversial results. In this sense, administration of indomethacin, as an inhibitor of prostaglandin synthesis, increased serum TNF-a concentration and exacerbated gastric mucosal damage in rats. Other authors indicated that indomethacin did not modify LPS-induced TNF-a release in mice. In the present study and in another, the effect of PGEj administered before D-GalN may have been different from that found in other studies in which it was administered after the induction of liver injury. Additionally, controversial results about the effect of PGE1 on TNF-a release may also be related to the model of liver injury (toxic, hepatitis, endotoxemia, etc).
The potential role of TNF-a in preventing liver injury is under investigation. In this sense, it has also been shown that preadministration of low doses of TNF-a is able to desensitize against murine endotoxic shock. TNF-a stimulates the secretion of several acute phase proteins in the liver. Also, preadministration of IL-1 or the nitric oxide donor sodium nitroprusside protects mice against endotoxic shock. In these studies, protection was also related to a stimulation of TNF-a release from peritoneal macrophages. Our data show that IL-1 a and nitric oxide do not seem to be directly involved in the protection by PGE1 during D-GalN liver injury. Nevertheless, it cannot be excluded that IL-1 a and/or nitric oxide may play a protective role during a more prolonged time (12 h) of D-GalN liver toxicity. Different studies are underway in which antibodies against TNF-a or inhibitors of inducible nitric oxide synthase are administered to elucidate the role of these inflammatory mediators during protection by PGEj on D-GalN liver injury.
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Stimulation of TNF-a but not IL-1 a release from inflammatory cells induced by D-GalN was correlated with an increase in hepatic damage. Protection against D-GalN-induced liver injury by preadministration of PGE1 was correlated with an additional increase of serum TNF-a but not IL-1 a concentration in serum. Further studies are required to confirm whether the priming effect of PGE1 on TNF-a release is responsible for prostanoid protection during experimental and therapeutic treatment of liver dysfunction.