title: Immunomodulatory activity of TNF-alpha during acute liver injury induced by D-galactosamine and its protection by PGE1 in rats.
abstract: Tumour necrosis factor-alpha (TNF-alpha) mediates hepatocyte cell death by D-galactosamine (D-GalN) and its protection by prostaglandin E(1) (PGE(1)). The activation of immune system plays an important role in the development of liver injury. TNF-alpha and PGE(1) 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-alpha during D-GalN-induced liver injury was related to an alteration by PGE(1) of the immunoregulatory activity of TNF-alpha. The role of TNF-alpha was assessed by anti-TNF-alpha antibodies to D-GalN-treated rats in the presence or absence of PGE(1). 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-alpha, IL-1alpha, IL-6 and IFN-gamma concentrations in blood. Anti-TNF-alpha antibodies abolished all immunological changes and greatly reduced liver damage induced by D-GalN. The protection by PGE(1) against D-GalN liver injury was associated with an increase in TNF-alpha concentration and a reduction of IL-1alpha 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-alpha antibodies abolished the protection by PGE(1) 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 PGE(1) or anti-TNF-alpha was associated with similar effects on the inflammatory parameters studied. Nevertheless, the abolishment of liver protection by PGE(1) with anti-TNF-alpha in D-GalN-treated rats in the presence of a protective cytokine profile suggests that the release of TNF-alpha induced by PGE(1) pre-administration was exerting a direct protective effect on hepatocytes against D-GalN injury. Consequently, the effect of PGE(1) on inflammatory parameters studied during liver injury was unrelated to TNF-alpha.
authors.affiliation: Unidad de Investigación, Unidad Clínica Aparato Digestivo, Hospital Universitario Reina Sofía, Av Menéndez Pidal s/n, Córdoba E-14004, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Lozano
authors.forename: Javier
authors.initials: J
authors.lastname: Padillo
authors.forename: José Luis
authors.initials: JL
authors.lastname: Montero
authors.forename: José
authors.initials: J
authors.lastname: Peña
authors.forename: Manuel
authors.initials: M
authors.lastname: De la Mata
authors.forename: Jordi
authors.initials: J
authors.lastname: Muntané
mesh_terms: D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D005688:Galactosamine / Q000633:toxicity*; D007371:Interferon-gamma / Q000097:blood; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000502:physiology*
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D007371:Interferon-gamma; D000527:Alprostadil