A novel technique for selective NF- B inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion

Hoffmann, Florian; Sass, Gabriele; Zillies, Jan; Zahler, Stefan; Tiegs, Gisa; Hartkorn, Andreas; Fuchs, Sebastian; Wagner, Jenny; Winter, Gerhard; Coester, Conrad; Gerbes, Alexander L.; Vollmar, Angelika M.

doi:10.1136/gut.2008.165647

Cited by 56 publications

(36 citation statements)

References 36 publications

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“…Previous research on rats has demonstrated that the inhibition of NF-κB activation in Kupffer cells reduces the production of pro-inflammatory cytokines, attenuates D-GlaN/LPS-induced liver damage, and improves survival, without affecting anti-apoptotic proteins in liver tissues (39). This raises the possibility that the hepatoprotective effect exerted by LXA4 observed in the present study is due to the inhibition of NF-κB in Kupffer cells.…”

Section: Discussionmentioning

confidence: 35%

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

Jiang

Jiang³

et al. 2016

International Journal of Molecular Medicine

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Abstract.Although rare, acute liver failure (ALF) is associated with high levels of mortality, warranting the development of novel therapies. Nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) play roles in ALF. Lipoxin A4 (LXA4) has been shown to alleviate inflammation in non-hepatic tissues. In the present study, we explored whether LXA4 exerted hepatoprotective effects in a rat model of ALF. A rat model of ALF was generated by intraperitoneal injections of D-galactosamine (300 mg/kg) and lipopolysaccharide (50 µg/kg). Animals were randomly assigned to: control group (no ALF); model group (ALF); and the groups treated with a low dose (0.5 µg/kg), medium dose (1 µg/kg), and high dose (2 µg/kg) of LXA4 (all with ALF); and pyrrolidine dithiocarbamate (PDTC)-treated group (ALF and 100 mg/kg PDTC, an inhibitor of NF-κB). Liver histology was measured using H&E staining, serum levels by ELISA, and liver mRNA expression was measured by RT-PCR for the detection of the pro-inflammatory cytokines TNF-α and IL-6. Liver cell apoptosis (as measured using the TUNEL method and examining caspase-3 activity), and Kupffer cell NF-κB activity [using an electrophoretic mobility shift assay (EMSA)] were examined. Serum levels of transaminases, TNF-α and interleukin-6 (IL-6) were substantially higher in the model group compared to controls. In the model group, significant increases in TNF-α and IL-6 mRNA expression, TUNEL-positive cells, and caspase-3 activity in the liver tissue were noted. LXA4 improved liver pathology and significantly decreased the indicators of inflammatory response and apoptosis in a dose-dependent manner. High-dose LXA4 provided better protection than PDTC. LXA4 administration significantly decreased NF-κB expression in hepatocytes and Kupffer cells. These results indicated that LXA4 inhibited NF-κB activation, reduced the secretion of pro-inflammatory cytokines, and inhibited apoptosis of liver cells, thereby exerting protective effects against ALF.

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Section: Discussionmentioning

confidence: 35%

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

Jiang

Jiang³

et al. 2016

International Journal of Molecular Medicine

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“…NF-κB activation in the resident liver macrophages causes increased expression of proinflammatory cytokines including IL-1β, TNF-α leading to inflammation and liver failure [25]. Moreover, liver injury can be reduced in experimental fulminant hepatitis by selectively targeting NF-κB in Küpffer cells [26] or by administrating pyrrolidine dithiocarbamate, a general NF-κB inhibitor, in GalN/LPS induced FHF [27]. Experiments with TNF-α or TNF-receptor p55 knockout mice further confirmed the critical role of TNF-α in LPS/ GalN-induced hepatotoxicity [28,29].…”

Section: Discussionmentioning

confidence: 99%

Reduced Hepatic Injury in Toll-Like Receptor 4–Deficient Mice Following D-Galactosamine/Lipopolysaccharide-Induced Fulminant Hepatic Failure

Ari

Avlas

Pappo³

et al. 2012

Cell Physiol Biochem

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Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), D-galactosamine (GalN)-induced FHF is a well established model of liver injury in mice. Toll-Like Receptor 4 (TLR4) has been identified as a receptor for LPS. The aim of this study was to investigate the role of TLR4 in FHF induced by D-GalN/LPS administration in mice. Wild type (WT) and TLR4 deficient (TLR4ko) mice were studied in vivo in a fulminant model induced by GalN/LPS. Hepatic TLR4 expression, serum liver enzymes, hepatic and serum TNF-α and interleukin-1β levels were determined. Apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor-kappaβ (NF-ĸ β) and phosphorylated c-Jun hepatic expression were studied using Western blot analysis. All WT mice died within 24 hours after administration of GalN/LPS while all TLR4ko mice survived. Serum liver enzymes, interleukin-1β, TNF-α level, TLR4 mRNA expression, hepatic injury and hepatocyte apoptosis all significantly decreased in TLR4ko mice compared with WT mice. A significant decrease in hepatic c-Jun and IĸB signaling pathway was noted in TLR4ko mice compared with WT mice. In conclusion, following induction of FHF, the inflammatory response and the liver injury in TLR4ko mice was significantly attenuated through decreased hepatic c-Jun and NF-ĸB expression and thus decreased TNF-α level. Down-regulation of TLR4 expression plays a pivotal role in GalN/LPS induced FHF. These findings might have important implications for the use of the anti TLR4 protein signaling as a potential target for therapeutic intervention in FHF.

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“…-labeled NF-B consensus sequence oligonucleotides (Promega, Heidelberg, Germany) as previously described [23]. Gels were exposed to Cyclone Storage Phosphor Screens (Canberra-Packard, Schwadorf, Austria) followed by analysis with a phosphor imager station (Cyclone Storage Phosphor System, Canberra-Packard).…”

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confidence: 99%

Helenalin bypasses Bcl-2-mediated cell death resistance by inhibiting NF-κB and promoting reactive oxygen species generation

Hoffmann

Schwarzenberg

López-Antón

et al. 2011

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractEvasion of cell death by overexpression of anti-apoptotic proteins, such as Bcl-2, is commonly observed in cancer cells leading to a lack of response to chemotherapy.Hence, there is a need to find new chemotherapeutic agents that are able to overcome chemoresistance mediated by Bcl-2 and to understand their mechanisms of action. Helenalin, a sesquiterpene lactone ( and free intracellular iron as mediators of helenalin-induced cell death whereas activation of JNK and abrogation of Akt activity did not contribute to helenalin-elicited cell death. Our results highlight the NF-κB inhibitor helenalin as a promising chemotherapeutic agent to overcome Bcl-2-induced cell death resistance.

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A novel technique for selective NF- B inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion

Abstract: Background and aims: The transcription factor nuclear factor kappa B (NF-kB)

Cited by 56 publications

References 36 publications

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

Reduced Hepatic Injury in Toll-Like Receptor 4–Deficient Mice Following D-Galactosamine/Lipopolysaccharide-Induced Fulminant Hepatic Failure

Helenalin bypasses Bcl-2-mediated cell death resistance by inhibiting NF-κB and promoting reactive oxygen species generation

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