Immunomodulatory activity of TNF-α during acute liver injury induced by D-galactosamine and its protection by PGE1 in rats

Abstract

Tumour necrosis factor-α (TNF-α) mediates hepatocyte cell death by D-galactosamine (D-GalN) and its protection by prostaglandin E1 (PGE1). The activation of immune system plays an important role in the development of liver injury. TNF-α and PGE1 regulate the activity and cytokine release of different inflammatory cells. The present study was undertaken to determine if the noxious or hepatic protective properties of TNF-α during D-GalN-induced liver injury was related to an alteration by PGE1 of the immunoregulatory activity of TNF-α. The role of TNF-α was assessed by anti-TNF-α antibodies to D-GalN-treated rats in the presence or absence of PGE1. D-GalN enhanced the percentage of monocytes and T lymphocytes in the total peripheral blood mononuclear cells (PBMCs). D-GalN enhanced the activation degree of monocytes, but reduced that of T lymphocytes. D-GalN also enhanced TNF-α, IL-1α, IL-6 and IFN-γ concentrations in blood. Anti-TNF-α antibodies abolished all immunological changes and greatly reduced liver damage induced by D-GalN. The protection by PGE1 against D-GalN liver injury was associated with an increase in TNF-α concentration and a reduction of IL-1α and IL-6. These changes were associated with a reduction of monocyte activation degree and a recovery of that of T lymphocytes. Although anti-TNF-α antibodies abolished the protection by PGE1 against D-GalN-liver injury, they did not essentially counteract the effect of the prostanoid in all immunological parameters studied. The present study showed that the protection against D-GalN liver damage by PGE1 or anti-TNF-α was associated with similar effects on the inflammatory parameters studied. Nevertheless, the abolishment of liver protection by PGE1 with anti-TNF-α in D-GalN-treated rats in the presence of a protective cytokine profile suggests that the release of TNF-α induced by PGE1 pre-administration was exerting a direct protective effect on hepatocytes against D-GalN injury. Consequently, the effect of PGE1 on inflammatory parameters studied during liver injury was unrelated to TNF-α. © 2002 Elsevier Science B.V. All rights reserved.