Inhibition of nuclear factor κB and phosphatidylinositol 3‐kinase/Akt is essential for massive hepatocyte apoptosis induced by tumor necrosis factor α in mice

Imose, Motoaki; Nagaki, Masahito; Naiki, Taku; Osawa, Yosuke; Brenner, David A.; Asano, Tomohiko; Hayashi, Hideki; Kato, Tomohiro; Moriwaki, Hisataka

doi:10.1034/j.1478-3231.2003.00867.x

Cited by 25 publications

(23 citation statements)

References 47 publications

(55 reference statements)

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“…Here we demonstrate that concomitant activation of PKB/Akt and NF-kB is necessary for the survival of endothelial cells exposed to TNF, implicating that in HUVEC these pathways are independently activated by TNF and elicit non-redundant survival responses. This was not an anticipated result, because in breast cancer cells inhibition of PKB/ Akt enhanced TNF toxicity indirectly by attenuating NF-kB activation (Burow et al, 2000), whereas hepatocytes resist to TNF-induced death with just one pathway active (Imose et al, 2003). b1 integrinmediated adhesion protects aggressive prostate cancer cells against anoikis or TNF via PKB/Akt-dependent upregulation of survivin (Fornaro et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

Bieler¹,

Hasmim²,

Monnier³

et al. 2007

Oncogene

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Section: Discussionmentioning

confidence: 99%

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

Bieler¹,

Hasmim²,

Monnier³

et al. 2007

Oncogene

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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%

“…For ribonuclease protection assay, frozen liver and spleen tissues from mice were homogenized in ISOGEN (Nippongene, Tokyo, Japan), and total RNA was isolated as described previously. 23 Ribonuclease protection assay was performed with the RibaQuant Multi-Probe Rnase Protection Assay System (Pharmingen, San Diego, CA) according to the manufacturer's instructions. Total RNA was hybridized with 32 P-labeled probes including cytokine genes synthesized by mCK-3b Multi-Probe template sets (Pharmingen).…”

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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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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“…14 Although livers of ob/ob mice exhibit increased sensitivity to bacterial lipopolysaccharide (LPS), 15 they instead resist T-cell-mediated cytotoxicity. 16 Ob/ob mice also have increased nuclear factor B (NF-B) activation, 12,13 which inhibits death receptor-mediated apoptosis [17][18][19] by inducing several anti-apoptotic factors. 17,20,21 However, the susceptibility of ob/ob mice to repeated alcohol intoxication has not been investigated so far.…”

mentioning

confidence: 99%

Alcohol increases tumor necrosis factor α and decreases nuclear factor‐κb to activate hepatic apoptosis in genetically obese mice†

Robin¹,

Demeilliers²,

Sutton³

et al. 2005

Hepatology

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Both obesity and alcohol can cause oxidative stress, cytokine induction, and steatohepatitis. To determine the consequences of their combination, we compared the hepatic effects of moderate ethanol binges in lean and obese ob/ob mice. Mice received water or ethanol (2.5 g/kg) by gastric intubation daily for 4 days, and were killed 2 hours after the last administration. Some obese mice also received pentoxifylline, an inhibitor of tumor necrosis factor-␣ (TNF-␣) production, before each ethanol administration. In lean mice, these moderate ethanol doses did not increase plasma TNF-␣ and hepatic caspase-3 activity, but triggered some apoptotic hepatocytes. Naive ob/ob mice had a few necrotic and apoptotic hepatocytes, but exhibited little oxidative stress, possibly because of adaptive increases in manganese superoxide dismutase, heat shock protein 70 (Hsp70), mitochondrial cytochrome c, and mitochondrial DNA. Alcohol administration to ob/ob mice did not increase oxidative stress despite increased CYP2E1, but increased plasma TNF-␣, further increased Hsp70, and profoundly decreased p65 nuclear factor B (NF-B) protein and DNA-binding activity in nuclear extracts. Caspase-3 was activated, and more apoptotic hepatocytes were found in intoxicated obese mice than naive obese mice. In intoxicated obese mice, pentoxifylline fully prevented the increase in plasma TNF-␣ the decrease in nuclear NF-B activity, and the increase in hepatic caspase-3, and it also decreased hepatic triglycerides. In conclusion, obese mice develop adaptations that may limit oxidative stress. Moderate ethanol intoxication does not increase oxidative stress in obese mice, but increases TNF-␣ and also decreases nuclear NF-B activity, thus unleashing the apoptotic effects of TNF-␣. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/ 0270-9139/suppmat/index.html). (HEPATOLOGY 2005;42:1280-1290

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Inhibition of nuclear factor κB and phosphatidylinositol 3‐kinase/Akt is essential for massive hepatocyte apoptosis induced by tumor necrosis factor α in mice

Abstract: The inducible activation of NF-kappaB and constitutive activation of Akt regulate hepatocyte survival against TNF-alpha, which occurs independent of Bcl-2 families.

Cited by 25 publications

References 47 publications

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

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

Alcohol increases tumor necrosis factor α and decreases nuclear factor‐κb to activate hepatic apoptosis in genetically obese mice†

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