Ethanol Decreases Inflammatory Response in Human Lung Epithelial Cells by Inhibiting the Canonical NF-kB-Pathway

Mörs, Katharina; Hörauf, Jason-Alexander; Kany, Shinwan; Wagner, Nils; Sturm, Ramona; Woschek, Mathias; Perl, Mario; Marzi, Ingo; Relja, Borna

doi:10.1159/000480313

Cited by 24 publications

(25 citation statements)

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“…In general, this setting is not comparable to our setting of an acute short-term exposure, which has been linked to the anti-inflammatory effects of ethanol [18]. Beside its capability of decreasing the pro-inflammatory cytokine levels in murine macrophages [38] or diminishing the adhesion of leukocytes to human lung epithelial cells [28], acute ethanol intake affects inflammasome activity. Upon acute ethanol administration, NLRP3 inflammasome activation was decreased by the inhibited oligomerization of ASC and lysosomal disruption [26].…”

Section: Discussionmentioning

confidence: 88%

“…Previous studies revealed significant anti-inflammatory effects of acute ethanol administration upon the induction of inflammatory processes in different cell entities including human lung epithelial cells [28,30], but also in hepatic and neuronal inflammation [17,31]. Despite its immense clinical relevance, the influence of an acute intoxication with ethanol on inflammatory processes mediated by inflammasomes is mechanistically poorly investigated.…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies, our group has demonstrated that acute/short exposure to ethanol attenuated the release of pro-inflammatory cytokines in vitro [28,29]. Recently, we figured out that acute/short exposure to ethanol decreased the inflammatory response by inhibiting the canonical pathway of NF-kB signaling in human lung epithelial cells in vitro [28], which also plays a central role in step 1 signaling of inflammasome activation [7]. The impact of the acute exposure of hepatic cells to ethanol is poorly investigated, and nothing is known about the possible interplay with inflammasomes.…”

Section: Introductionmentioning

confidence: 94%

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Short Exposure to Ethanol Diminishes Caspase-1 and ASC Activation in Human HepG2 Cells In Vitro

Hörauf

Kany

Janicova

et al. 2020

IJMS

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This paper discusses how the assembly of pro-caspase-1 and apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) in macromolecular protein complexes, inflammasomes, activates caspase-1. The present study investigates the molecular mechanisms of inflammasome activation in HepG2 cells and examines how short exposures to ethanol (EtOH) affect inflammasome activation. HepG2 cells were treated with lipopolysaccharide (LPS), ATP or nigericin (NIG) in a two-step model. After LPS priming, ATP or NIG were added. As inhibitors, sodium orthovanadate (general inhibitor of tyrosine phosphatases), AC-YVAD-CMK (caspase-1 inhibitor) or AZ10606120 (purinergic receptor P2X7R inhibitor) were applied after LPS priming. To monitor the inflammasome activation, the caspase-1 activity, ASC speck formation, reactive oxygen species (ROS) production and cell death were analyzed. To elucidate the mechanistical approach of EtOH to the inflammasome assembly, the cells were treated with EtOH either under simultaneous LPS administration or concurrently with ATP or NIG application. The co-stimulation with LPS and ATP induced a significant ASC speck formation, caspase-1 activation, cell death and ROS generation. The inhibition of the ATP-dependent purinoreceptor P2X7 decreased the caspase-1 activation, whereas sodium orthovanadate significantly induced caspase-1. Additional treatment with EtOH reversed the LPS and ATP-induced caspase-1 activation, ASC speck formation and ROS production. The ASC speck formation and caspase-1 induction require a two-step signaling with LPS and ATP in HepG2 cells. Inflammasome activation may depend on P2X7. The molecular pathway of an acute effect of EtOH on inflammasomes may involve a reduction in ROS generation, which in turn may increase the activity of tyrosine phosphatases.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

Short Exposure to Ethanol Diminishes Caspase-1 and ASC Activation in Human HepG2 Cells In Vitro

Hörauf

Kany

Janicova

et al. 2020

IJMS

Self Cite

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“…As a consequence, IIR may lead to sepsis, systemic inflammatory response syndrome and multiple organ dysfunction syndrome [2]. IIR is also known to cause acute lung injury which in turn leads to a condition known as acute respiratory distress syndrome and contributes to the high mortality associated with IIR [3-5].…”

Section: Introductionmentioning

confidence: 99%

Nrf2 Activation Induced by Sirt1 Ameliorates Acute Lung Injury After Intestinal Ischemia/Reperfusion Through NOX4-Mediated Gene Regulation

Chai

Zhang

Shen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Nuclear erythroid 2-related factor-2 (Nrf2) is a major stress-response transcription factor that has been implicated in regulating ischemic angiogenesis. We investigated the effects of Nrf2 in regulating revascularization and modulating acute lung injury. Methods: The expression of Nrf2 and sirtuin1 (Sirt1) was assessed in lung tissue by western blotting and immunofluorescence staining after intestinal ischemia/reperfusion (IIR) in Nrf2–/– and wild-type (WT) mice. The involvement of Nrf2 in angiogenesis, cell viability, and migration was investigated in human pulmonary microvascular endothelial cells (PMVECs). Additionally, the influence of Nrf2 expression on NOX pathway activation was measured in PMVECs after oxygen–glucose deprivation/reoxygenation. Results: We found activation and nuclear accumulation of Nrf2 in lung tissue after IIR. Compared to IIR in WT mice, IIR in Nrf2–/– mice significantly enhanced leukocyte infiltration and collagen deposit, and inhibited endothelial cell marker CD31 expression. Nrf2 upregulation and translocation into the nucleus stimulated by Sirt1 overexpression exhibited remission of histopathologic changes and enhanced CD31 expression. Nrf2 knockdown repressed non-phagocytic cell oxidase 4 (NOX4), hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) expression after IIR. Nrf2 upregulation by Sirt1 enhances NOX4, HIF-1α and VEGF expression after IIR in WT mice. Furthermore, Nrf2 knockdown suppressed cell viability, capillary tube formation and cell migration in PMVECs after oxygen–glucose deprivation/reoxygenation and also inhibited NOX4, HIF-1 and VEGF expression. Moreover, NOX4 knockdown in PMVECs decreased the levels of VEGF, HIF-1α and angiogenesis. Conclusion: Nrf2 stimulation by Sirt1 plays an important role in sustaining angiogenic potential through NOX4-mediated gene regulation.

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“…That we found a significant increase in alcohol-induced microglial apoptosis in our rodent model of acute alcohol use suggests the short-and long-term neurotoxic effects of alcohol use may be due in part to reductions in the reparative activity of microglia. Interestingly, alcohol could reduced Inflammatory Response in Human Lung Epithelial Cells [48].…”

Section: Discussionmentioning

confidence: 95%

Salt-Inducible Kinase 1 (SIK1) is Induced by Alcohol and Suppresses Microglia Inflammation via NF-κB Signaling

Zhang

Gao

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Alcohol consumption has been shown to cause neuroinflammation and increase a variety of immune-related signaling processes. Microglia are a crucial part of alcohol-induced neuroinflammation and undergo apoptosis. Even though the importance of these inflammatory processes in the effects of alcohol-related neurodegeneration have been established, the mechanism of alcohol-induced microglia apoptosis is unknown. In prior research, we discovered that alcohol increases expression of salt-inducible kinase 1 (SIK1) in rodent brain tissue. In this study, we sought to determine what role SIK1 expression plays in alcohol-induced neuroinflammation as well as whether and by what mechanism it regulates microglia apoptosis. Methods: Adult C57BL/6 mice were divided into four groups and for 3 weeks treated with either 0%, 5%, 10%, or 15% alcohol during 3 hour periods. The mice were sacrificed and their brains excised for analysis. Additionally, primary microglia were isolated from neonatal mice. SIK1 expression in alcohol-treated brain tissue and microglia was analyzed via RT-PCR and western blotting. TUNEL staining, caspase-3, and caspase-9 activity assays were performed to evaluate microglial apoptosis. Cell fluorescence staining and NF-κB luciferase activity assays were used to evaluate the effects of SIK1 expression on the NF-κB signaling pathway. Results: SIK1 expression was increased in the brains of mice that consumed alcohol, and this effect was seen in mouse primary microglia. SIK1 knockdown in microglia increased alcohol-induced apoptosis in these cells. Furthermore, SIK1 reduced NF-κB signaling pathway factors, and SIK1 knockdown in microglia promoted alcohol-induced NF-κB activity. TUNEL staining, caspase-3, and caspase-9 activity assays consistently revealed that alcohol-induced microglial apoptosis was inhibited by depletion of p65. Finally, we determined that NF-κB signaling is required for alcohol-induced, SIK1-mediated apoptosis in microglia. Conclusion: This study establishes for the first time not only that SIK1 is crucial to regulating alcohol-induced microglial apoptosis, but also that the NF-κB signaling pathway is required for its activity. Overall, our results help elucidate mechanisms of alcohol-induced neuroinflammation.

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Ethanol Decreases Inflammatory Response in Human Lung Epithelial Cells by Inhibiting the Canonical NF-kB-Pathway

Cited by 24 publications

References 60 publications

Short Exposure to Ethanol Diminishes Caspase-1 and ASC Activation in Human HepG2 Cells In Vitro

Short Exposure to Ethanol Diminishes Caspase-1 and ASC Activation in Human HepG2 Cells In Vitro

Nrf2 Activation Induced by Sirt1 Ameliorates Acute Lung Injury After Intestinal Ischemia/Reperfusion Through NOX4-Mediated Gene Regulation

Salt-Inducible Kinase 1 (SIK1) is Induced by Alcohol and Suppresses Microglia Inflammation via NF-κB Signaling

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