CD39-mediated ATP-adenosine signalling promotes hepatic stellate cell activation and alcoholic liver disease

Eur J Pharmacol. 2021 Aug 15;905:174198. doi: 10.1016/j.ejphar.2021.174198. Epub 2021 May 24.

Abstract

CD39 is associated with diverse physiological and pathological processes, including cell proliferation and differentiation. Adenosine triphosphate (ATP) is hydrolysed to adenosine by different enzymes including ecto-nucleoside triphosphate diphosphohydrolase-1/ENTPD1 (CD39) and ecto-5'-nucleotidase (CD73), regulating many physiological and pathological processes in various diseases, but these changes and functions in alcoholic liver disease are generally unknown. In this study, an alcoholic liver disease model in vivo was induced by ethanol plus carbon tetrachloride(CCl4) administered to C57BL/6 mice, who were the intraperitoneally injected with the CD39 inhibitor sodium polyoxotungstate (POM1) or colchicine from the 5th week to the 8th week. Meanwhile, hepatic stellate cells were stimulated by acetaldehyde to replicate alcoholic liver fibrosis models in vitro. Exogenous ATP and POM1 were added in turn to the culture system. Pharmacological blockade of CD39 largely prevents liver damage and collagen deposition. We found that blockade or silencing of CD39 prevented acetaldehyde-induced proliferation of HSC-T6 cells and the expression of fibrogenic factors. Moreover, blockade or silencing of CD39 could block the activation of the adenosine A2A and adenosine A2B receptors and the TGF-β/Smad3 pathway, which are essential events in HSC activation. Thus, blockade of CD39 to inhibit the transduction of ATP to adenosine may prevent HSC activation, alleviating alcoholic hepatic fibrosis. The findings from this study suggest ATP-adenosine signalling is a novel therapeutic and preventive target for alcoholic liver disease.

Keywords: ATP; Alcoholic hepatic disease; CD39; Hepatic stellate cell activation; TGF-β/Smad3 pathway.

MeSH terms

  • 5'-Nucleotidase / genetics
  • 5'-Nucleotidase / metabolism
  • Acetaldehyde / toxicity
  • Adenosine / metabolism*
  • Adenosine Triphosphate / metabolism*
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Apyrase / antagonists & inhibitors
  • Apyrase / genetics
  • Apyrase / metabolism*
  • Carbon Tetrachloride / toxicity
  • Colchicine / pharmacology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Ethanol / toxicity
  • Gene Knockdown Techniques
  • Hepatic Stellate Cells / metabolism*
  • Humans
  • Liver Diseases, Alcoholic / etiology*
  • Liver Diseases, Alcoholic / metabolism*
  • Liver Diseases, Alcoholic / pathology
  • Mice, Inbred C57BL
  • Primary Cell Culture
  • Rats
  • Receptor, Adenosine A2A / metabolism
  • Receptor, Adenosine A2B / metabolism
  • Signal Transduction / drug effects*
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / metabolism
  • Tungsten Compounds / pharmacology

Substances

  • Antigens, CD
  • Cytokines
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A2B
  • Smad3 Protein
  • Transforming Growth Factor beta
  • Tungsten Compounds
  • Ethanol
  • Adenosine Triphosphate
  • Carbon Tetrachloride
  • 5'-Nucleotidase
  • Apyrase
  • CD39 antigen
  • Acetaldehyde
  • Adenosine
  • Colchicine