Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression
| Autor: | Aisha Nair, Greg J. Beitel, Jacob I. Sznajder, Iiro Taneli Helenius, Humberto E. Trejo Bittar, Peter H. S. Sporn |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Chemokine Antimicrobial peptides Gene Expression CCL2 Biology Biochemistry Article Cell Line Analytical Chemistry Hypercapnia 03 medical and health sciences Alkaloids Immune system Genes Reporter Animals Humans Luciferases Interleukin 6 Chemokine CCL2 Innate immune system Interleukin-6 Macrophages AMPK Epithelial Cells Carbon Dioxide High-Throughput Screening Assays Cell biology Drosophila melanogaster 030104 developmental biology Cell culture Immunology biology.protein Molecular Medicine Antimicrobial Cationic Peptides Biotechnology |
| Zdroj: | SLAS Discovery. 21:363-371 |
| ISSN: | 2472-5552 |
| DOI: | 10.1177/1087057115624091 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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