TY - JOUR
T1 - Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression
AU - Helenius, Iiro Taneli
AU - Nair, Aisha
AU - Bittar, Humberto E Trejo
AU - Sznajder, Jacob I.
AU - Sporn, Peter H S
AU - Beitel, Greg J.
N1 - Funding Information:
We thank Andrew Rennekamp for comments on the manuscript; the members of the ICCB-Longwood screening facility, especially Su Chiang and Dave Wrobel; the members of the Harvard Drosophila RNAi Screening Center (DRSC); and the members of the Northwestern Center for Molecular Innovation and Drug Discovery (CMIDD), especially Gary Schiltz and Karl Scheidt. We also thank the DRSC for plasmids and Lynn Welch for operational support. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the NIH to GJB and PHSS (NHLBI/R01-HL107629), to JIS (NHLBI/R01-HL-85534), to ICCB-Longwood (NERCE/NSRB U54-AI057159), and to DRSC (NIGMS/R01-GM067761); from the American Heart Association to GJB (grant-in-aid award, 0855686G) and to ITH (predoctoral fellowship, 0715562Z); from the Chicago Biomedical Consortium with support from The Searle Funds at The Chicago Community Trust to NU CMIDD; and from the Northwestern University Robert H. Lurie Comprehensive Cancer Center to the NU HTA core facility.
Publisher Copyright:
© 2015 Society for Laboratory.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
KW - anti-infective drugs
KW - cell-based assays
KW - immune system diseases
KW - reporter gene assays
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U2 - 10.1177/1087057115624091
DO - 10.1177/1087057115624091
M3 - Article
C2 - 26701099
AN - SCOPUS:84961241775
SN - 1087-0571
VL - 21
SP - 363
EP - 371
JO - Journal of Biomolecular Screening
JF - Journal of Biomolecular Screening
IS - 4
ER -
