TNF signaling

Mann, Amrit; Czaja, Mark J.; Schattenberg, Jörn M.

doi:10.1002/9781118663387.ch14

Cited by 3 publications

(6 citation statements)

References 157 publications

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“…C). Levels of proteins that mediate hepatocyte resistance to TNF‐dependent apoptosis such as cIAP1, cIAP2, SOD2, and Bcl‐X L were unaffected by VLX103 (Fig. D).…”

Section: Resultsmentioning

confidence: 97%

“…Hepatic toxicity from GalN/LPS occurs through the classical TNF death cascade of caspase 8‐mediated Bid cleavage into tBid, which translocates to mitochondria to trigger cytochrome c release, effector caspase cleavage, and apoptosis . Decreased TUNEL positivity suggested that VLX103 blocked TNF‐induced apoptosis at some point along this pathway.…”

Section: Resultsmentioning

confidence: 99%

“…Inflammatory mediators such as TNF promote hepatocellular injury in alcoholic hepatitis, ischemia/reperfusion, nonalcoholic steatohepatitis, viral hepatitis and fulminant hepatic failure . Anti‐inflammatory therapies might therefore be effective in liver diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Macrophage‐produced TNF triggers hepatocyte apoptosis through TNF receptor 1. The cascade of events in this hepatocyte death pathway includes initiator caspase 8 activation, cleavage of the pro‐apoptotic Bcl‐2 family member Bid to tBid, and translocation of tBid to the mitochondrial membrane to trigger the release of apoptogenic factors such as cytochrome c that activate effector executioner caspases 3 and 7 . The hepatic inflammatory response is therefore a potential therapeutic target to prevent activation of this death pathway in toxin‐induced liver disease.…”

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confidence: 99%

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Pentamidine blocks hepatotoxic injury in mice

Zhao¹,

Ilyas

Cingolani

et al. 2017

Hepatology

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Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the D-galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells and mortality as compared to vehicle-injected controls. VLX103 decreased GalN/LPS induction of TNF but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS-treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7 which resulted from reduced c-Jun N-terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 h after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol-induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL-positive cells. Conclusion VLX103 effectively decreases toxin-induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease.

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“…C). Levels of proteins that mediate hepatocyte resistance to TNF‐dependent apoptosis such as cIAP1, cIAP2, SOD2, and Bcl‐X L were unaffected by VLX103 (Fig. D).…”

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Pentamidine blocks hepatotoxic injury in mice

Zhao¹,

Ilyas

Cingolani

et al. 2017

Hepatology

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“…Inflammation was abrogated in Nlrp3 A350V mice with the TNF but not IL‐17 knockout. These findings delineate a new mechanism by which TNF acts as a central mediator of liver disease …”

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confidence: 99%

Inflammasome‐mediated inflammation and fibrosis: It is more than just the IL‐1β

Amir

Czaja

2017

Hepatology

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Decreased Hepatocyte Autophagy Leads to Synergistic IL‐1β and TNF Mouse Liver Injury and Inflammation

et al. 2020

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Background and Aims The proinflammatory cytokine IL‐1β has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL‐1β promotes liver injury in these diseases is unclear, as no IL‐1β receptor‐linked death pathway has been identified. Autophagy functions in hepatocyte resistance to injury and death, and findings of decreased hepatic autophagy in many liver diseases suggest a role for impaired autophagy in disease pathogenesis. Recent findings that autophagy blocks mouse liver injury from lipopolysaccharide led to an examination of autophagy’s function in hepatotoxicity from proinflammatory cytokines. Approach and Results AML12 cells with decreased autophagy from a lentiviral autophagy‐related 5 (Atg5) knockdown were resistant to toxicity from TNF, but sensitized to death from IL‐1β, which was markedly amplified by TNF co‐treatment. IL‐1β/TNF death was necrosis by trypan blue and propidium iodide positivity, absence of mitochondrial death pathway and caspase activation, and failure of a caspase inhibitor or necrostatin‐1s to prevent death. IL‐1β/TNF depleted autophagy‐deficient cells of ATP, and ATP depletion and cell death were prevented by supplementation with the energy substrate pyruvate or oleate. Pharmacological inhibitors and genetic knockdown studies demonstrated that IL‐1β/TNF‐induced necrosis resulted from lysosomal permeabilization and release of cathepsins B and L in autophagy‐deficient cells. Mice with a tamoxifen‐inducible, hepatocyte‐specific Atg5 knockout were similarly sensitized to cathepsin‐dependent hepatocellular injury and death from IL‐1β/TNF in combination, but neither IL‐1β nor TNF alone. Knockout mice had increased hepatic inflammation, and IL‐1β/TNF‐treated, autophagy‐deficient AML12 cells secreted exosomes with proinflammatory damage–associated molecular patterns. Conclusions The findings delineate mechanisms by which decreased hepatocyte autophagy promotes IL‐1β/TNF‐induced necrosis from impaired energy homeostasis and lysosomal permeabilization and inflammation through the secretion of exosomal damage–associated molecular patterns.

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TNF signaling

Cited by 3 publications

References 157 publications

Pentamidine blocks hepatotoxic injury in mice

Pentamidine blocks hepatotoxic injury in mice

Inflammasome‐mediated inflammation and fibrosis: It is more than just the IL‐1β

Decreased Hepatocyte Autophagy Leads to Synergistic IL‐1β and TNF Mouse Liver Injury and Inflammation

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