Activation of NF‐κ<scp>B</scp> after chronic ethanol intake and haemorrhagic shock/resuscitation in mice

Maraslioglu, Miriam; Weber, Regina; Korff, Sebastian; Blattner, Carolin; Nauck, C; Henrich, Dirk; Jobin, Christian; Marzi, Ingo; Lehnert, Mark

doi:10.1111/bph.12224

Cited by 14 publications

(20 citation statements)

References 52 publications

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“…Despite numerous reports on the deleterious effects of chronic or excessive alcohol abuse, others and our group have reported that moderate or acute use may exert beneficial effects (15)(16)(17)20,36). The negative effects of alcohol consumption have been linked to an increased inflammatory response, including increased cytokine release (14,15,37,38). Pro-inflammatory cytokines such as IL-1β, TNF, IL-6 and IL-8 have been identified as important contributors to the pathogenesis of organ damage, including lung as well as liver injury in models of acute inflammation (17)(18)(19)(39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Ethanol, ethyl and sodium pyruvate decrease the inflammatory responses of human lung epithelial cells via Akt and NF-κB in vitro but have a low impact on hepatocellular cells

Relja

Omid

Wagner

et al. 2015

International Journal of Molecular Medicine

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Abstract. Increases in pro-inflammatory cytokine levels and tissue-infiltrating leukocytes have been closely linked to increased systemic and local inflammation, which result in organ injury. Previously, we demonstrated the beneficial and hepatoprotective anti-inflammatory effects of acute ethanol (EtOH) ingestion in an in vivo model of acute inflammation. Due to its undesirable side-effects, however, EtOH does not represent a therapeutic option for treatment of acute inflammation. Therefore, in this study, we compared the effects of acute EtOH exposure with ethyl pyruvate (EtP) as an alternative anti-inflammatory drug in an in vitro model of hepatic and pulmonary inflammation. Human hepatocellular carcinoma cells Huh7 and alveolar epithelial cells A549 were stimulated with either interleukin (IL) IL-1β (1 ng/ml, 24 h) or tumor necrosis factor (TNF) (10 ng/ml, 4 h), and then treated with EtP (2.5-10 mM), sodium pyruvate (NaP, 10 mM) or EtOH (85-170 mM) for 1 h. IL-6 or IL-8 release from Huh7 or A549 cells, respectively, was measured by an enzyme-linked immunosorbent assay. Neutrophil adhesion to cell monolayers and CD54 expression were also analyzed. Bcl-2 and Bax gene expression was determined by RT-qPCR, and western blot analysis was performed to determine the mechanisms involved. Treating A549 cells with either EtOH or EtP significantly reduced the IL-1β-or TNF-induced IL-8 release, whereas treating Huh7 cells did not significantly alter IL-6 release. Similarly, neutrophil adhesion to stimulated A549 cells was significantly reduced by EtOH or EtP, whereas for Huh7 cells the tendency for reduced neutrophil adhesion rates by EtOH or EtP was not significant. CD54 expression was noticeably reduced in A549 cells, but this was not the case in Huh7 cells after treatment. The Bax/ Bcl-2 ratio was dose-dependently decreased by EtOH and by high-dose EtP in A549 cells, indicating a reduction in apoptosis, whereas this effect was not observed in Huh7 cells. The underlying mechanisms involve reduced phosphorylation of Akt and nuclear factor-κB (NF-κB) p65. We noted that as with EtP, EtOH reduced the inflammatory response in lung epithelial cells under acute inflammatory conditions. However, due to the low impact which EtP and EtOH had on the hepatocellular cells, our data suggest that both substances exerted different effects depending on the cellular entity. The possible underlying mechanisms involved the downregulation of Akt and the transcription factor NF-κB, but further research on this subject is required.

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Section: Discussionmentioning

confidence: 99%

Ethanol, ethyl and sodium pyruvate decrease the inflammatory responses of human lung epithelial cells via Akt and NF-κB in vitro but have a low impact on hepatocellular cells

Relja

Omid

Wagner

et al. 2015

International Journal of Molecular Medicine

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“…Control pair-fed animals received the equal amount of maltodextrin-supplemented diet (ctrl), in order to warrantee the isocaloric feeding. In alcohol-fed animals, the diet protocol consisted of a gradual increase in the EtOH dose in the liquid diet, beginning with 1.75% (v/v) for 5 days, and increasing to 2.63%, 3.50%, 4.38%, and 6.3% (v/v) as described before[ 20 , 25 ]. After 4 weeks of feeding, animals were weighted and allocated to hemorrhage and subsequent resuscitation group (H/R) or the control (sham) group[ 20 ].…”

Section: Methodsmentioning

confidence: 99%

“…Numerous harmful pathophysiological changes directly affecting the liver, including steatosis, steatohepatitis, fibrosis or cirrhosis, are closely associated with the chronic ethanol intoxication[ 19 ]. These changes occurring in the setting of chronic ethanol-use cause an increased susceptibility to H/R-induced liver injury[ 20 , 21 ]. The underlying mechanisms involve at least in part increased NF-κB activation resulting in enhanced production of local proinflammatory cytokines, including IL-6 and increased infiltration of the liver with neutrophils, resulting in organ damage[ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…These changes occurring in the setting of chronic ethanol-use cause an increased susceptibility to H/R-induced liver injury[ 20 , 21 ]. The underlying mechanisms involve at least in part increased NF-κB activation resulting in enhanced production of local proinflammatory cytokines, including IL-6 and increased infiltration of the liver with neutrophils, resulting in organ damage[ 20 , 21 ]. Additionally, JNK activation partly contributes to an enhanced hepatotoxicity after chronic alcohol feeding[ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Differential Relevance of NF-κB and JNK in the Pathophysiology of Hemorrhage/Resususcitation-Induced Liver Injury after Chronic Ethanol Feeding

et al. 2015

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BackgroundChronic ethanol (EtOH) abuse worsens pathophysiological derangements after hemorrhagic shock and resuscitation (H/R) that induce hepatic injury and strong inflammatory changes via JNK and NF-κB activation. Inhibiting JNK with a cell-penetrating, protease-resistant peptide D-JNKI-1 after H/R in mice with healthy livers ameliorated these effects. Here, we studied if JNK inhibition by D-JNKI-1 in chronically EtOH-fed mice after hemorrhagic shock prior to the onset of resuscitation also confers protection.MethodsMale mice were fed a Lieber-DeCarli diet containing EtOH or an isocaloric control (ctrl) diet for 4 weeks. Animals were hemorrhaged for 90 min (32 ± 2 mm Hg) and randomly received either D-JNKI-1 (11 mg/kg, intraperitoneally, i. p.) or sterile saline as vehicle (veh) immediately before the onset of resuscitation. Sham animals underwent surgical procedures without H/R and were either D-JNKI-1 or veh treated. Two hours after resuscitation, blood samples and liver tissue were harvested.ResultsH/R induced hepatic injury with increased systemic interleukin (IL)-6 levels, and enhanced local gene expression of NF-κB-controlled genes such as intercellular adhesion molecule (ICAM)-1 and matrix metallopeptidase (MMP)9. c-Jun and NF-κB phosphorylation were increased after H/R. These effects were further increased in EtOH-fed mice after H/R. D-JNKI-1 application inhibited the proinflammatory changes and reduced significantly hepatic injury after H/R in ctrl-fed mice. Moreover, D-JNKI-1 reduces in ctrl-fed mice the H/R-induced c-Jun and NF-κB phosphorylation. However, in chronically EtOH-fed mice, JNK inhibition did not prevent the H/R-induced hepatic damage and proinflammatory changes nor c-Jun and NF-κB phosphorylation after H/R.ConclusionsThese results indicate, that JNK inhibition is protective only in not pre-harmed liver after H/R. In contrast, the pronounced H/R-induced liver damage in mice being chronically fed with ethanol cannot be prevented by JNK inhibition after H/R and seems to be under the control of NF-κB.

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“…NF-κB, however, is involved in the control of the transcription of many genes whose functions extend beyond the immune response, but are involved in more general stress responses [ 17 ]. Various physiological stress conditions such as liver regeneration and hemorrhagic shock can activate NF-κB [ 18 , 19 ]. Also physical stress, in the form of irradiation as well as oxidative stress to cells, induces NF-κB, that in turn activates a large variety of stress response genes [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Exploring the Potential of Venom from Nasonia vitripennis as Therapeutic Agent with High-Throughput Screening Tools

Danneels

Formesyn

Graaf

2015

Toxins

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The venom from the ectoparasitoid wasp Nasonia vitripennis (Hymenoptera: Pteromalidae) contains at least 80 different proteins and possibly even more peptides or other small chemical compounds, demonstrating its appealing therapeutic application. To better understand the dynamics of the venom in mammalian cells, two high-throughput screening tools were performed. The venom induced pathways related to an early stress response and activated reporters that suggest the involvement of steroids. Whether these steroids reside from the venom itself or show an induced release/production caused by the venom, still remains unsolved. The proinflammatory cytokine IL-1β was found to be down-regulated after venom and LPS co-treatment, confirming the anti-inflammatory action of N. vitripennis venom. When analyzing the expression levels of the NF-κB target genes, potentially not only the canonical but also the alternative NF-κB pathway can be affected, possibly explaining some counterintuitive results. It is proposed that next to an NF-κB binding site, the promoter of the genes tested by the PCR array may also contain binding sites for other transcription factors, resulting in a complex puzzle to connect the induced target gene with its respective transcription factor. Interestingly, Nasonia venom altered the expression of some drug targets, presenting the venom with an exciting therapeutical potential.

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Activation of NF‐κB after chronic ethanol intake and haemorrhagic shock/resuscitation in mice

Cited by 14 publications

References 52 publications

Ethanol, ethyl and sodium pyruvate decrease the inflammatory responses of human lung epithelial cells via Akt and NF-κB in vitro but have a low impact on hepatocellular cells

Ethanol, ethyl and sodium pyruvate decrease the inflammatory responses of human lung epithelial cells via Akt and NF-κB in vitro but have a low impact on hepatocellular cells

Differential Relevance of NF-κB and JNK in the Pathophysiology of Hemorrhage/Resususcitation-Induced Liver Injury after Chronic Ethanol Feeding

Exploring the Potential of Venom from Nasonia vitripennis as Therapeutic Agent with High-Throughput Screening Tools

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