Reduced Susceptibility of Nonobese Diabetic Mice to TNF-α and<scp>d</scp>-Galactosamine-Mediated Hepatocellular Apoptosis and Lethality

Bahjat, Frances R.; Dharnidharka, Vikas R.; Fukuzuka, Kunitaro; Morel, Laurence; Crawford, James M.; Clare‐Salzler, Michael; Moldawer, Lyle L.

doi:10.4049/jimmunol.165.11.6559

Cited by 29 publications

(29 citation statements)

References 34 publications

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“…In contrast, all ICR mice survived, indicating their resistance to TNF-a/GalN-induced liver failure ( Figure 1a) (Po0.0001 for overall comparison). Although NOD was less sensitive to TNF-a/GalN than B6 (Po0.0001) as reported previously, 21 its genetic background ICR was more resistant (Po0.0001 as compared to B6) ( Figure 1a). According to these results, we decided to compare B6 and ICR mice to investigate their intrinsic sensitivity to TNF-a/GalN-induced liver failure.…”

Section: Resultssupporting

confidence: 81%

Intrinsic resistance to TNF-α-induced hepatocyte apoptosis in ICR mice correlates with expression of a short form of c-FLIP

Takai

Nagaki

Imao

et al. 2007

Laboratory Investigation

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The administration of tumor necrosis factor-a (TNF-a) or the anti-Fas antibody (Jo-2) to mice causes acute liver failure, which is lethal within hours as a result of the induction of apoptosis in hepatocytes. It was recently reported that nonobese diabetic (NOD) mice are less sensitive to TNF-a/D-galactosamine (GalN)-induced liver failure than C57BL/6J (B6) mice, whereas both NOD and B6 mice were sensitive to the lethal effect of Jo-2. In the present study, we investigated the differences between the apoptotic liver cell death induced by TNF-a/GalN and that induced by Jo-2. B6, NOD, and JclImperial Cancer Research (ICR) mice were injected intravenously with TNF-a/GalN or Jo-2. ICR mice were less sensitive to TNF-a/GalN-induced liver failure than NOD and B6 mice (Po0.0001). In contrast, ICR mice were more sensitive to Jo-2-induced liver failure than B6 mice (P ¼ 0.0003). The liver caspase-3, -8 activity, serum transaminase levels, and the number of apoptotic liver nuclei all decreased in ICR in comparison to B6 mice treated with TNF-a/GalN. The mRNA expression of TNFR-associated death domain, Fas associated protein with death domain, and Bcl family and nuclear factor-kB activation induced by TNF-a/GalN were similar in both mice. Interestingly, the short form of cellular FLICE/caspase-8-inhibitory protein (c-FLIP S ) was constitutively upregulated in ICR mice. In conclusion, these results suggest that ICR mice have an intrinsic resistance to TNF-a-induced hepatocyte apoptosis, and that c-FLIP S may play a role in TNF-a/GalN-induced liver failure, but not in Fas-induced liver failure.

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Section: Resultssupporting

confidence: 81%

Intrinsic resistance to TNF-α-induced hepatocyte apoptosis in ICR mice correlates with expression of a short form of c-FLIP

Takai

Nagaki

Imao

et al. 2007

Laboratory Investigation

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“…No apoptosis was detected by TUNEL assay in livers from control group. Extensive apoptosis was found in the liver sections of mice treated with LPS/D-Gal, which is consistent with previous studies using the models of LPS-induced fulminant hepatitis (26,36). Few apoptotic nuclei were found in the liver sections from Ad.GFP-infected mice without treatment.…”

Section: Adenoviral Infection-induced Tnf-␣ Tolerance Decreases Liversupporting

confidence: 91%

“…H&E staining of liver sections revealed noticeable leukocyte infiltration in the livers of Ad.GFPinfected mice, which is not observed in normal livers (data not shown). Treatment of control mice with LPS/D-Gal resulted in extensive hemorrhage and necrosis in the livers typical for LPSinduced fulminant hepatitis (26,36). The extent of liver hemorrhage and necrosis was substantially lower, albeit not eliminated in Ad.GFP-infected mice following LPS/D-Gal treatment (data not shown).…”

Section: Adenoviral Infection-induced Tnf-␣ Tolerance Decreases Livermentioning

confidence: 99%

Adenoviral Infection Decreases Mortality from Lipopolysaccharide-Induced Liver Failure Via Induction of TNF-α Tolerance

Yarovinsky

Powers

Butler

et al. 2003

The Journal of Immunology

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Effects of adenoviral infection on in vivo responses to LPS mediated by TNF-α were evaluated in a murine model. Adenovirus-infected mice showed decreased mortality from fulminant hepatitis induced by administration of LPS or staphylococcal enterotoxin B in the presence of D-galactosamine. Importantly, TNF-α resistance genes within adenoviral E3 region were not required, because E1,E3-deleted vectors showed similar effects. Adenovirus-infected mice exhibited higher TNF-α levels after LPS stimulation, no difference in TNFR1 expression, and similar mortality from Fas-induced fulminant hepatitis. Decreased production of IL-6 and KC in response to exogenous TNF-α, in addition to protection from TNF-α, suggested that adenoviral infection results in TNF-α tolerance.

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“…60 Conversely, cytotoxic signals are transduced into the hepatocytes, and massive hepatocyte death ensues. 57,61 Therefore, liver dysfunction characterized by significantly elevated serum ALT and AST concentrations and rapid death within 9 hours are the typical findings in D-galN sensitization models of shock caused by SAgs.…”

Section: Discussionmentioning

confidence: 99%

Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

Tilahun

Marietta

et al. 2011

The American Journal of Pathology

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Among the exotoxins produced by Staphylococcus aureus and Streptococcus pyogenes, the superantigens (SAgs) are the most potent T-cell activators known to date. SAgs are implicated in several serious diseases including toxic shock syndrome (TSS), Kawasaki disease, and sepsis. However, the immunopathogenesis of TSS and other diseases involving SAgs are still not completely understood. The commonly used conventional laboratory mouse strains do not respond robustly to SAgs in vivo. Therefore, they must be artificially rendered susceptible to TSS by using sensitizing agents such as D-galactosamine (D-galN), which skews the disease exclusively to the liver and, hence, is not representative of the disease in humans. SAg-induced TSS was characterized using transgenic mice expressing HLA class II molecules that are extremely susceptible to TSS without D-galN. HLA-DR3 transgenic mice recapitulated TSS in humans with extensive multiple-organ inflammation affecting the lung, liver, kidneys, heart, and small intestines. Heavy infiltration with T lymphocytes (both CD4 ؉ and CD8؉), neutrophils, and macrophages was noted. In particular, the pathologic changes in the small intestines were extensive and accompanied by significantly altered absorptive functions of the enterocytes. In contrast to massive liver failure alone in the D-galN sensitization model of TSS, findings of the present study suggest that gut dysfunction might be a key pathogenic event that leads to high morbidity and mortality in humans with

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

Cited by 29 publications

References 34 publications

Intrinsic resistance to TNF-α-induced hepatocyte apoptosis in ICR mice correlates with expression of a short form of c-FLIP

Intrinsic resistance to TNF-α-induced hepatocyte apoptosis in ICR mice correlates with expression of a short form of c-FLIP

Adenoviral Infection Decreases Mortality from Lipopolysaccharide-Induced Liver Failure Via Induction of TNF-α Tolerance

Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

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