Tumor Necrosis Factor α Prevents Tumor Necrosis Factor Receptor—Mediated Mouse Hepatocyte Apoptosis, But Not Fas–Mediated Apoptosis: Role of Nuclear Factor–κB

Nagaki, Masahito; Naiki, Taku; Brenner, David A.; Osawa, Yosuke; Imose, Motoaki; Hayashi, Hideki; Banno, Yoshiko; Nakashima, Shigeru; Moriwaki, Hisataka

doi:10.1053/jhep.2000.20239

Cited by 69 publications

(62 citation statements)

References 31 publications

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“…22,23 Because of missense mutations at phosphorylation sites where serines 32 and 36 are replaced with alanines, the mutant I B irreversibly binds to NF-B and prevents its activation. The viral solution containing 2 ϫ 10 9 plaque-forming units was injected in mice intravenously.…”

Section: Methodsmentioning

confidence: 99%

“…Nuclear extracts of the livers and intrahepatic T cells were prepared as described previously. 22 NF-B-binding consensus single-strand oligonucleotide (5Ј-TAGTTGAGGGG-ACTTTCCCAGG-3Ј) was first annealed with the complement oligonucleotide (5Ј-TGCCTGGGAAAG-TCCCCTCAACTA-3Ј). The annealed DNA fragment was labeled with [␣-32 P]dCTP (ICN Biochemicals, Costa Mesa, CA) using Klenow DNA polymerase.…”

Section: Methodsmentioning

confidence: 99%

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Leflunomide protects from T-cell-mediated liver injury in mice through inhibition of nuclear factor κB

et al. 2004

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Leflunomide is a novel immunosuppressive and anti-inflammatory agent for the treatment of autoimmune disease. The aim of this study was to investigate whether leflunomide protects from liver injury induced by concanavalin A (Con A), a T-cell-dependent model of liver damage. BALB/c mice were injected with 25 mg/kg Con A in the presence or absence of 30 mg/kg leflunomide. Liver injury was assessed biochemically and histologically. Levels of circulating cytokines and expressions of cytokine messenger RNA (mRNA) in the liver and the spleen were determined. Treatment with leflunomide markedly reduced serum transaminase activities and the numbers of dead liver cells. Leflunomide significantly inhibited increases in plasma tumor necrosis factor alpha (TNF-␣) and interleukin 2 concentrations, and also reduced TNF-␣ mRNA expression in the liver after administration of Con A. These findings were supported by the results in which leflunomide administration decreased the number of T lymphocytes infiltrating the liver as well as inhibiting their production of TNF-␣. Activation of nuclear factor B (NF-B), which regulates TNF-␣ production, was inhibited in the liver of mice treated with leflunomide, resulting in a reduction of TNF-␣ production from lymphocytes infiltrating the liver. In conclusion, leflunomide is capable of regulating T-cell-mediated liver injury in vivo and that this event may depend on the decrease of TNF-␣ production in the liver through inhibition of NF-B activation caused by leflunomide.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Leflunomide protects from T-cell-mediated liver injury in mice through inhibition of nuclear factor κB

et al. 2004

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“…However, NF-B also suppresses TNF-mediated hepatocyte apoptosis 20 [70,71], complicating the use of NF-B inhibitors for therapeutic purposes. Interestingly, adenovirus-mediated expression of ABIN-1 in the liver, but not of an IB superrepressor in which the IKK phosphorylation sites have been mutated [72], completely prevented lethality in the TNF/galactosamine-induced murine model of acute liver failure, which was associated with a significant decrease in TNF-induced leukocyte infiltration and hepatocyte apoptosis [45]. This indicates that the anti-apoptotic effect of ABIN-1 is dominant compared to its potential apoptosis sensitizing effect due to the inhibition of NF-B dependent expression of survival genes in the liver.…”

Section: Abins In Diseasementioning

confidence: 99%

ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling

Verstrepen¹,

Carpentier²,

Verhelst³

et al. 2009

Biochemical Pharmacology

161

126

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ABINs have been described as three different proteins (ABIN-1, ABIN-2, that bind the ubiquitin-editing nuclear factor-B (NF-B) inhibitor protein A20 and which show limited sequence homology. Overexpression of ABINs inhibits NF-B activation by tumor necrosis factor (TNF) and several other stimuli. Similar to A20, ABIN-1 and ABIN-3 expression is NF-B dependent, implicating a potential role for the A20/ABIN complex in the

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“…24,32 However, NF-kB was similarly induced either in ICR mice or B6 mice after TNF-a/GalN injection ( Figure 7), indicating that NF-kB-related anti-apoptotic signaling is equally induced in both mice, as well as that TNF-a induces NF-kB activation through TNFR1. It is well known that the adapter protein TRADD binds to TNFR1 and serves as anchor for the subsequent recruitment of other proteins into the signaling complex that directly lead to cell death or NF-kB induction.…”

Section: Discussionmentioning

confidence: 94%

“…24 Nuclear extracts were frozen and stored at À801C until use. Protein concentrations were measured by Bradford method.…”

Section: Nuclear Extracts and Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

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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Tumor Necrosis Factor α Prevents Tumor Necrosis Factor Receptor—Mediated Mouse Hepatocyte Apoptosis, But Not Fas–Mediated Apoptosis: Role of Nuclear Factor–κB

Cited by 69 publications

References 31 publications

Leflunomide protects from T-cell-mediated liver injury in mice through inhibition of nuclear factor κB

Leflunomide protects from T-cell-mediated liver injury in mice through inhibition of nuclear factor κB

ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling

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

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