Immunomodulatory activity of TNF-a during acute liver injury induced by D-galactosamine and its protection by PGE 1 in rats Jose ´ Manuel Lozano a , Javier Padillo b , Jose ´ Luis Montero a , Jose ´ Pen ˜a c , Manuel De la Mata a , Jordi Muntane ´ a, * a Unidad de Investigacio ´n, Unidad Clı ´nica Aparato Digestivo, Hospital Universitario Reina Sofı ´a, Av. Mene ´ndez Pidal s/n, Co ´rdoba E-14004, Spain b Servicio Cirugı ´a, Hospital Universitario Reina Sofı ´a, Co ´rdoba, Spain c Servicio Inmunologı ´a, Hospital Universitario Reina Sofı ´a, Co ´rdoba, Spain Received 27 March 2002; accepted 4 November 2002 Abstract Tumour necrosis factor-a (TNF-a) 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-a 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-a during D-GalN-induced liver injury was related to an alteration by PGE 1 of the immunoregulatory activity of TNF-a. The role of TNF-a was assessed by anti-TNF-a 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-a, IL-1a, IL-6 and IFN-g concentrations in blood. Anti-TNF-a 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-a concentration and a reduction of IL-1a 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-a 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-a was associated with similar effects on the inflammatory parameters studied. Nevertheless, the abolishment of liver protection by PGE 1 with anti-TNF-a in D-GalN-treated rats in the presence of a protective cytokine profile suggests that the release of TNF-a 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-a. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Liver injury; TNF-a; IL-1a; IL-6; IFN-g; Monocytes; T lymphocytes; PGE 1 1567-5769/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII:S1567-5769(02)00259-X Abbreviations: D-GalN, D-galactosamine; PBS, phosphate buffer solution; PBMC, peripheral blood mononuclear cells; PGE 1 , prostaglandin E 1 ; ALT, alanine aminotransferase; TNF-a, tumour necrosis factor-a; IL-1a, interleukin-1a; IL-6, interleukin-6; IFN-g, interferon-g; FHF, fulminant hepatic failure; RPE, phycoeritrine; FITC, fluorescein; ELISA, enzyme-linked immunosorbent assay. * Corresponding author. Tel.: +34-957-011070; fax: +34-957-010452. E-mail address: jmuntane@hrs.sas.junta-andalucia.es (J. Muntane ´). www.elsevier.com/locate/intimp International Immunopharmacology 3 (2003) 197 – 207