Tumor necrosis factor receptor p55 is essential for intrahepatic granuloma formation and hepatocellular apoptosis in a murine model of bacterium-induced fulminant hepatitis

Abstract

Accumulating evidence implicates tumor necrosis factor (TNF) and Fas systems in liver injury, although the interaction between these two systems remains to be investigated. In this study, we examined Propionibacterium acnes-primed TNF receptor p55-deficient (TNFRp55 ؊/؊) or Fas-deficient MRL/MpJ Lpr/Lpr mice challenged with lipopolysaccharide (LPS). Priming with P. acnes caused mononuclear cell infiltration into the hepatic lobules and granuloma formation in the livers of TNFRp55 wild-type mice. Subsequent LPS challenge caused massive liver injury and a marked increase in transaminase levels, leading to acute lethality in control wild-type mice. In contrast, the same treatment caused few pathological changes in livers of TNFRp55 ؊/؊ mice, and all animals survived. P. acnes and subsequent LPS challenge induced granuloma formation and apoptotic changes, respectively, in livers of MRL/MpJ Lpr/Lpr mice. However, liver injury was 50% of that in control MRL/MpJ ؉/؉ mice, suggesting some role of the Fas-Fas ligand system in this liver injury model. On the other hand, an agonistic anti-Fas antibody caused massive apoptosis and hemorrhagic changes of the liver without any priming with P. acnes, leading to death in both TNFRp55 ؊/؊ and control wild-type mice. These results suggest that TNFRp55 but not Fas was involved in P. acnes-induced granuloma formation as well as subsequent LPS-induced liver injury and that TNFRp55 and Fas independently induced apoptosis of hepatocytes in vivo. MATERIALS AND METHODS Experimental reagents. LPS (Escherichia coli serotype O55:B5) was obtained from Difco Laboratories (Detroit, Mich.). P. acnes (ATCC 11828) was heat killed and lyophilized as previously described (19). A purified hamster monoclonal agonistic anti-Fas antibody (Jo2) was purchased from Pharmingen (San Diego, Calif.). Animals. TNFRp55 Ϫ/Ϫ mice ([C57BL/6 ϫ 129]F 1) were generated as previously described (32) and bred under pathogen-free conditions at the Animal Research Center of Kanazawa University. MRL/MpJ Lpr/Lpr (hereafter called Lpr/Lpr) and MRL/MpJ ϩ/ϩ (hereafter called ϩ/ϩ) mice were obtained from Sankyo Laboratories (Tokyo, Japan) and CLEA Japan Inc. (Tokyo, Japan), respectively. Eight-to 16-week-old TNFRp55 ϩ/ϩ (hereafter called the wild type) and homozygous TNFRp55 Ϫ/Ϫ mice or 6-to 7-week-old ϩ/ϩ and Lpr/Lpr mice were used for the experiments. All animal procedures in this study complied with the standards set forth in the guidelines for the care and use of laboratory animals on the Takara-machi Campus of Kanazawa University.

CD8+ T-cell-mediated response to Listeria monocytogenes taken up in the liver and replicating within hepatocytes

“…It is relevant to note that both TNF-a and IFN-g can induce apoptosis by murine hepatocytes in culture (49-51); fragmentation of hepatocyte DNA and liver failure were also detected in mice administered TNF-a (49,51). Furthermore, both TNF-a and IFN-g were implicated in apoptosis of hepatocytes and liver damage found in several murine models of fulminating hepatitis (52)(53)(54). On the other hand, we reported that IFN-g inhibited the replication of Listeria within hepatocytes both in vivo and in vitro (40).…”

Redox manipulation using the thiol-oxidizing agent diethyl maleate prevents hepatocellular necrosis and apoptosis in a rodent endotoxemia model

“…However, in studies using TNF as the inflammatory stimulus, DEM caused similar protection against the initiation of apoptosis, suggesting a direct PMN-independent effect of thiol oxidation on the TNF-induced apoptosis in hepatocytes. 34,35 In this regard, Kim et al recently reported that induction of heat shock protein 70 through GSH oxidation by S-nitroso-N-acetylpenicillamine protected cultured rat hepatocytes from TNF-␣-induced apoptosis. 36 The time course of hsp70 induction by S-nitroso-N-acetylpenicillamine was too slow to account for the protection observed in the present studies.…”

Mycophenolate mofetil prevents lethal acute liver failure in mice induced by bacille Calmette‐Guérin and lipopolysaccharide

“…First, the administration of BCG induces infiltration of mononuclear cells into the liver lobules. 16,17 Second, subsequent injection of LPS activates mononuclear cells, triggering the release of various soluble factors which are toxic for the liver, such as TNF-a, 10,18,19 IL-1, 20,21 and IFN-g. 19,22,23 Finally, a burst of cytokine production results in severe liver injury. In addition, activated T cells have been shown to be involved in the pathogenesis of this acute liver failure.…”