title: Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression.
abstract: 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.
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Iiro Taneli
authors.initials: IT
authors.lastname: Helenius
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Aisha
authors.initials: A
authors.lastname: Nair
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Humberto E Trejo
authors.initials: HE
authors.lastname: Bittar
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
authors.forename: Peter H S
authors.initials: PH
authors.lastname: Sporn
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA beitel@northwestern.edu.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Beitel
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D002245:Carbon Dioxide / Q000037:antagonists & inhibitors* / Q000633:toxicity; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D004331:Drosophila melanogaster / Q000166:cytology / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D015870:Gene Expression; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays; D006801:Humans; D006935:Hypercapnia / Q000517:prevention & control; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology
chemical_list: D000470:Alkaloids; D023181:Antimicrobial Cationic Peptides; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C508600:IL6 protein, human; D015850:Interleukin-6; D002245:Carbon Dioxide; D008156:Luciferases
keywords: anti-infective drugs; cell-based assays; immune system diseases; reporter gene assays