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

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

Author information

1
Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
2
Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
3
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.
4
Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA beitel@northwestern.edu.

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.

KEYWORDS:

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

PMID:
26701099
PMCID:
PMC5096368
DOI:
10.1177/1087057115624091
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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