Lipopolysaccharide and<scp>d</scp>-galactosamine-induced hepatic injury is mediated by TNF-α and not by Fas ligand

Josephs, Michael D.; Bahjat, Frances R.; Fukuzuka, Kunitaro; Ksontini, Riadh; Solórzano, Carmen C.; Edwards, Carl K.; Tannahill, Cynthia L.; MacKay, Sally L. D.; Copeland, Edward M.; Moldawer, Lyle L.

doi:10.1152/ajpregu.2000.278.5.r1196

Cited by 102 publications

(87 citation statements)

References 45 publications

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“…Interestingly, it has been shown that Kupffer cell depletion results in an increase in circulating TNF-␣ (84). As TNF-␣ mediates apoptosis in Kupffer and endothelial cells (85,86), increased levels of TNF-␣ in IRF-2 Ϫ/Ϫ mice after LPS treatment may contribute to the significantly increased number of apoptotic Kupffer cells measured at 6 h after LPS challenge. This notion is supported by our observation that injection of recombinant TNF-␣ recapitulates this effect.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Lipopolysaccharide Sensitivity by IFN Regulatory Factor-2

Cuesta

Salkowski

Thomas

et al. 2003

The Journal of Immunology

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IFN regulatory factors (IRFs) are a family of transcription factors and include several members that regulate expression of pro- and anti-inflammatory genes. Mice with a targeted mutation in IRF-2 (IRF-2−/−) were studied after injection of LPS to evaluate the importance of IRF-2 in the regulation of endotoxicity. IRF-2−/− mice were highly refractory to LPS-induced lethality. Although hepatic TNF-α mRNA and circulating TNF-α were significantly elevated in LPS-challenged IRF-2−/− mice, levels of IL-1, IL-12, and IFN-γ mRNA and protein, as well as IL-6 protein, were significantly lower than levels seen in LPS-challenged IRF-2+/+ mice. IRF-2−/− mice were also more refractory to TNF-α challenge than were control mice, which was consistent with their diminished sensitivity to LPS, yet no significant difference in the mRNA expression of TNFRs was observed. IL-12Rβ2 mRNA levels from LPS-challenged IRF-2−/− mice were significantly different after 1, 6, and 8 h, suggesting that both diminished IL-12 and altered IL-12R expression contribute to the paucity of IFN-γ produced. IRF-2 knockout mice also failed to sustain LPS-inducible levels of IRF-1 and IFN consensus sequence binding protein mRNA expression, two transacting factors required for IL-12 transcription, perhaps as a result of diminished IL-1β, IL-6, and IFN-γ levels. Liver sections from IRF-2+/+ and IRF-2−/− mice were analyzed 6 h after a typically lethal injection of LPS. IRF-2−/− mice exhibited greater numbers of apoptotic Kupffer cells than did wild-type mice, suggesting a novel anti-apoptotic role for IRF-2. Collectively, these findings reveal a critical role for IRF-2 in endotoxicity, and point to a previously unappreciated role for IRF-2 in the regulation of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Regulation of Lipopolysaccharide Sensitivity by IFN Regulatory Factor-2

Cuesta

Salkowski

Thomas

et al. 2003

The Journal of Immunology

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“…6 -8 To investigate mechanisms of cytokine-dependent liver injury, mice can be sensitized with the hepatocytespecific transcriptional inhibitor D-galactosamine (GalN) in combination with the macrophage activator lipopolysaccharide (LPS). 9 In this GalN/LPS model, mice develop severe liver injury, which is dependent on tumor necrosis factor (TNF) 10,11 and interferon ␥ (IFN-␥) 12 induction, while interleukin (IL) 10 prevents injury. 13 In the present study we show that HO-1, induced by CoPP, protects mice from GalN/LPS-induced liver injury, prolongs survival, and reduces cytokine expression.…”

Section: Egradation Of Heme By Heme Oxygenases (Hos)mentioning

confidence: 99%

Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

et al. 2004

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Induction of the heme-degrading enzyme heme oxygenase-1 (HO-1) has been shown to be beneficial in terms of improvement of liver allograft survival and prevention of CD95-mediated apoptosis in the liver. In the present study, we investigated the effects of HO-1, and its products carbon monoxide (CO), biliverdin (BV), and iron/ferritin, in a mouse model of results in the production of carbon monoxide (CO), free iron, and biliverdin (BV). HO-1, in contrast to the second isoform HO-2, is inducible by various stimuli. 1,2 To investigate HO effects in vitro as well as in vivo, HO-1 can be induced by application of cobalt-protoporphyrin-IX (CoPP), for example, while tin-protoporphyrin-IX (SnPP) suppresses HO activity. 3,4 In the liver, administration of CoPP to mice results in HO-1 expression in hepatocytes as well as in Kupffer cells. 5 In vivo, HO-1 induction has been shown previously to protect mice from apoptotic liver damage 5 and to protect rats from liver graft rejection as well as from ischemia/reperfusion injury. 6 -8 To investigate mechanisms of cytokine-dependent liver injury, mice can be sensitized with the hepatocytespecific transcriptional inhibitor D-galactosamine (GalN) in combination with the macrophage activator lipopolysaccharide (LPS). 9 In this GalN/LPS model, mice develop severe liver injury, which is dependent on tumor necrosis factor (TNF) 10,11 and interferon ␥ (IFN-␥) 12 induction, while interleukin (IL) 10 prevents injury. 13 In the present study we show that HO-1, induced by CoPP, protects mice from GalN/LPS-induced liver injury, prolongs survival, and reduces cytokine expression. Protection from liver damage could also be achieved by pretreatment with the HO products CO and BV, but not by ferritin. Prolongation of survival and cytokine reduction was only detectable in mice pretreated with a combination of both hepatoprotective products CO and BV. Materials and MethodsAnimals. BALB/c-mice (6-8 weeks old; weight range, 18-22 g) were obtained from the animal facilities of the

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“…It was also shown that NOD mice produced lower levels of TNF-␣ than did most other strains, even though TNF-␣ gene expression was similar among these strains. To determine whether the differences in survival could be explained by a differential TNF-␣ production, serum TNF-␣ concentrations were determined at 90 min, a time period previously shown to represent the peak serum appearance after LPS administration (25). As shown in Fig.…”

Section: Lps/d-galactosamine-induced Lethality and Tnf-␣ Production Imentioning

confidence: 99%

“…This time was chosen, based on our previous work, because it preceded death but was a time period associated with significant liver injury (25,26). Livers were harvested; one lobe was homogenized for caspase-3-like activity, and another lobe was fixed in 10% buffered formalin for sectioning.…”

Section: Apoptosis and Liver Toxicity In Lps/d-galactosamine Treated mentioning

confidence: 99%

Reduced Susceptibility of Nonobese Diabetic Mice to TNF-α andd-Galactosamine-Mediated Hepatocellular Apoptosis and Lethality

Bahjat¹,

Dharnidharka

Fukuzuka³

et al. 2000

The Journal of Immunology

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Nonobese diabetic (NOD/LtJ or NOD) mice are resistant to doses of LPS and d-galactosamine that uniformly produce lethality in C57BL/6J (B6) mice (p < 0.01). Liver caspase-3-like activity, serum transaminase levels (both p < 0.05), and the numbers of apoptotic liver nuclei were also reduced in NOD compared with B6 mice treated with LPS (100 ng) and d-galactosamine (8 mg). NOD mice were also at least 100-fold more resistant to recombinant human TNF-α and d-galactosamine treatment than B6 mice (p < 0.001). Binding of recombinant human TNF-α to splenocytes from NOD mice was similar to that seen in B6 mice, suggesting that the defect in responsiveness was not due to an inability of recombinant human TNF-α to bind the NOD TNF type 1 (p55) receptor. Because the TNF type 1 (p55) receptor shares a common signaling pathway with Fas (CD95), NOD and B6 mice were treated with the Fas agonist antibody, Jo-2. Surprisingly, NOD mice were as sensitive as B6 mice to Fas-induced lethality and hepatic injury. In addition, primary hepatocytes isolated from NOD mice and cultured in vitro in the presence of d-galactosamine with or without TNF-α were found to be resistant to apoptosis and cytotoxicity when compared with B6 mice. In contrast, Jo-2 treatment produced similar increases in caspase-3 activity and cytotoxicity in primary hepatocytes from NOD and B6 mice. The resistance to LPS- and TNF-α-mediated lethality and hepatic injury in d-galactosamine-sensitized NOD mice is apparently due to a post-TNFR binding defect, and independent of signaling pathways shared with Fas.

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Lipopolysaccharide andd-galactosamine-induced hepatic injury is mediated by TNF-α and not by Fas ligand

Cited by 102 publications

References 45 publications

Regulation of Lipopolysaccharide Sensitivity by IFN Regulatory Factor-2

Regulation of Lipopolysaccharide Sensitivity by IFN Regulatory Factor-2

Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

Reduced Susceptibility of Nonobese Diabetic Mice to TNF-α andd-Galactosamine-Mediated Hepatocellular Apoptosis and Lethality

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