Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression

J Biomol Screen. 2016 Apr;21(4):363-71. doi: 10.1177/1087057115624091. Epub 2015 Dec 23.


Patients with severe lung disease may develop hypercapnia, elevation of the levels of CO2 in the lungs and blood, which is associated with increased risk of death, often from infection. To identify compounds that ameliorate the adverse effects of hypercapnia, we performed a focused screen of 8832 compounds using a CO2-responsive luciferase reporter in Drosophila S2* cells. We found that evoxine, a plant alkaloid, counteracts the CO2-induced transcriptional suppression of antimicrobial peptides in S2* cells. Strikingly, evoxine also inhibits hypercapnic suppression of interleukin-6 and the chemokine CCL2 expression in human THP-1 macrophages. Evoxine's effects are selective, since it does not prevent hypercapnic inhibition of phagocytosis by THP-1 cells or CO2-induced activation of AMPK in rat ATII pulmonary epithelial cells. The results suggest that hypercapnia suppresses innate immune gene expression by definable pathways that are evolutionarily conserved and demonstrate for the first time that specific CO2 effects can be targeted pharmacologically.

Keywords: anti-infective drugs; cell-based assays; immune system diseases; reporter gene assays.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / pharmacology*
  • Animals
  • Antimicrobial Cationic Peptides / agonists
  • Antimicrobial Cationic Peptides / antagonists & inhibitors
  • Antimicrobial Cationic Peptides / genetics
  • Antimicrobial Cationic Peptides / immunology
  • Carbon Dioxide / antagonists & inhibitors*
  • Carbon Dioxide / toxicity
  • Cell Line
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / immunology
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / immunology
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects*
  • Epithelial Cells / immunology
  • Gene Expression
  • Genes, Reporter
  • High-Throughput Screening Assays*
  • Humans
  • Hypercapnia / prevention & control
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Luciferases / genetics
  • Luciferases / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Macrophages / immunology


  • Alkaloids
  • Antimicrobial Cationic Peptides
  • CCL2 protein, human
  • Chemokine CCL2
  • IL6 protein, human
  • Interleukin-6
  • Carbon Dioxide
  • Luciferases