Anti-inflammatory Effects of Alcohol Are Associated with JNK-STAT3 Downregulation in an In Vitro Inflammation Model in HepG2 Cells

TY - JOUR

T1 - Anti-inflammatory Effects of Alcohol Are Associated with JNK-STAT3 Downregulation in an In Vitro Inflammation Model in HepG2 Cells

AU - Mörs, Katharina

AU - Sturm, Ramona

AU - Hörauf, Jason-Alexander

AU - Kany, Shinwan

AU - Cavalli, Paola

AU - Omari, Jazan

AU - Powerski, Maciej

AU - Surov, Alexey

AU - Marzi, Ingo

AU - Nowak, Aleksander J

AU - Relja, Borna

N1 - Copyright © 2021 Katharina Mörs et al.

PY - 2021

Y1 - 2021

N2 - Background: In several preclinical and in vitro models of acute inflammation, alcohol (ethanol, EtOH) has been described as an immunomodulatory agent. Similarly, in different pathologies, clinical observations have confirmed either pro- or anti-inflammatory effects of EtOH. The liver plays an important role in immunity and alcohol metabolism; therefore, we analysed dose- and time-dependent effects of EtOH on the inflammatory response of human liver cells in an in vitro model of acute inflammation.Methods: HepG2 cells were stimulated with IL-1β and subsequently exposed to EtOH in a low or high dose (85 mM, LoD or 170 mM, HiD) for 1 h (acute exposure) or 72 h (prolonged exposure). IL-6 and TNF-α release was determined by ELISA. Cell viability, adhesion of isolated neutrophils to HepG2 monolayers, their ICAM-1 expression, and the activation of stress-induced protein kinase/c-Jun N-terminal kinase (SAPK/JNK) or signal transducer and activator of transcription 3 (STAT3) were analysed.Results: In this experimental design, EtOH did not markedly change the cell viability. Acute and prolonged exposure to EtOH significantly reduced dose-independent IL-1β-induced IL-6 and TNF-α release, as well as adhesion capacity to pretreated HepG2 cells. Acute exposure to EtOH significantly decreased the percentage of ICAM-1-expressing cells. IL-1β stimulation notably increased the activation of SAPK/JNK. However, low-dose EtOH exposure reduced this activation considerably, in contradiction to high-dose EtOH exposure. Acute exposure to LoD EtOH significantly diminished the IL-1β-induced STAT3 activation, whereas an acute exposure of cells to either HiD EtOH or in a prolonged setting showed no effects on STAT3 activation.Conclusion: EtOH exerts anti-inflammatory potential in this in vitro model of hepatic inflammation. These effects are associated with the reduced activation of JNK/STAT3 by EtOH, particularly in the condition of acute exposure to low-dose EtOH.

AB - Background: In several preclinical and in vitro models of acute inflammation, alcohol (ethanol, EtOH) has been described as an immunomodulatory agent. Similarly, in different pathologies, clinical observations have confirmed either pro- or anti-inflammatory effects of EtOH. The liver plays an important role in immunity and alcohol metabolism; therefore, we analysed dose- and time-dependent effects of EtOH on the inflammatory response of human liver cells in an in vitro model of acute inflammation.Methods: HepG2 cells were stimulated with IL-1β and subsequently exposed to EtOH in a low or high dose (85 mM, LoD or 170 mM, HiD) for 1 h (acute exposure) or 72 h (prolonged exposure). IL-6 and TNF-α release was determined by ELISA. Cell viability, adhesion of isolated neutrophils to HepG2 monolayers, their ICAM-1 expression, and the activation of stress-induced protein kinase/c-Jun N-terminal kinase (SAPK/JNK) or signal transducer and activator of transcription 3 (STAT3) were analysed.Results: In this experimental design, EtOH did not markedly change the cell viability. Acute and prolonged exposure to EtOH significantly reduced dose-independent IL-1β-induced IL-6 and TNF-α release, as well as adhesion capacity to pretreated HepG2 cells. Acute exposure to EtOH significantly decreased the percentage of ICAM-1-expressing cells. IL-1β stimulation notably increased the activation of SAPK/JNK. However, low-dose EtOH exposure reduced this activation considerably, in contradiction to high-dose EtOH exposure. Acute exposure to LoD EtOH significantly diminished the IL-1β-induced STAT3 activation, whereas an acute exposure of cells to either HiD EtOH or in a prolonged setting showed no effects on STAT3 activation.Conclusion: EtOH exerts anti-inflammatory potential in this in vitro model of hepatic inflammation. These effects are associated with the reduced activation of JNK/STAT3 by EtOH, particularly in the condition of acute exposure to low-dose EtOH.

KW - Anti-Inflammatory Agents/pharmacology

KW - Cell Adhesion/drug effects

KW - Cell Survival/drug effects

KW - Down-Regulation

KW - Ethanol/pharmacology

KW - Hep G2 Cells

KW - Humans

KW - Intercellular Adhesion Molecule-1/metabolism

KW - Interleukin-6/metabolism

KW - MAP Kinase Kinase 4/metabolism

KW - Neutrophils/drug effects

KW - STAT3 Transcription Factor/metabolism

KW - Signal Transduction

KW - Tumor Necrosis Factor-alpha/metabolism

U2 - 10.1155/2021/6622701

DO - 10.1155/2021/6622701

M3 - SCORING: Journal article

C2 - 33791043

VL - 2021

SP - 6622701

JO - DIS MARKERS

JF - DIS MARKERS

SN - 0278-0240

ER -