Yonsei Med J.  2020 Jun;61(6):533-541. 10.3349/ymj.2020.61.6.533.

Ethanol Augments Monosodium Urate-Induced NLRP3 Inflammasome Activation via Regulation of AhR and TXNIP in Human Macrophages

Affiliations
  • 1Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
  • 2Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu, Korea

Abstract

Purpose
Ethanol elicits several inflammatory responses and affects the innate immune response. The aim of this study was to identify the mechanism by which ethanol affects uric acid-induced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation by regulation of aryl hydrocarbon receptor (AhR) and thioredoxin-interacting protein (TXNIP).
Materials and Methods
Human myeloid leukemia cells (U937 cells) were used to assess the role of ethanol in NLRP3 inflammasome activation induced by monosodium urate (MSU) crystals. Expression of target molecules, such as NLRP3 inflammasome components, AhR, and TXNIP, were measured using quantitative real-time PCR and Western blot analyses. The effect of ethanolinduced TXNIP on the NLRP3 inflammasome was assessed in human macrophages transfected with TXNIP siRNA.
Results
U937 cells treated with 100 mM ethanol for 24 h induced NLRP3 and interleukin (IL)-1β expression. Ethanol increased reactive oxygen species generation in a time- and dose-dependent manner. AhR mRNA expression was downregulated in U937 cells treated with 100 mM ethanol, whereas CYP1A1 mRNA expression increased. Treatment with ethanol increased NLRP3 and IL-1β mRNA and protein expression in U937 cells exposed to 1.0 mg/mL of MSU crystals for 24 h. TXNIP expression in U937 cells incubated with both 100 mM ethanol and 1.0 mg/mL of MSU crystals was significantly higher than in cells incubated with MSU crystals alone. Treatment with 100mM ethanol for 24 h downregulated NLRP3 and IL-1β expression in MSU crystal-activated U937 cells transfected with TXNIP siRNA, compared to those with scramble siRNA.
Conclusion
Ethanol stimulates uric acid-induced NLRP3 inflammasome activation through regression of AhR and upregulation of TXNIP.

Keyword

Ethanol; uric acid; NLRP3; inflammasome; AhR; TXNIP
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