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Suppression of inflammation response by a novel A 3 adenosine receptor agonist thio-Cl-IB-MECA through inhibition of Akt and NF-κB signaling

Title
Suppression of inflammation response by a novel A 3 adenosine receptor agonist thio-Cl-IB-MECA through inhibition of Akt and NF-κB signaling
Authors
Lee H.-S.Chung H.-J.Lee H.W.Jeong L.S.Lee S.K.
Ewha Authors
정낙신이혁우
Issue Date
2011
Journal Title
Immunobiology
ISSN
0171-2985JCR Link
Citation
vol. 216, no. 9, pp. 997 - 1003
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Adenosine, a purine nucleoside, is released from metabolically active cells into extracellular space and plays an important role in various pathophysiological processes. Adenosine regulates many biological responses including inflammation by the interaction with their receptors such as A 1, A 2A, A 2B, and A 3. Especially, A 3 adenosine receptor (A 3AR) is considered to be expressed in macrophage cells. To the end, A 3AR agonists have been reported to have an anti-inflammatory activity. In our continuous efforts to develop new anti-inflammatory agents, we found a novel adenosine analog, 2-chloro-N 6-(3-iodobenzyl)-4′-thioadenosine-5′-N-methyluronamide (thio-Cl-IB-MECA), was a potent human A 3AR agonist. The study was designed to investigate whether thio-Cl-IB-MECA has an anti-inflammatory potential in mouse macrophage RAW 264.7 cells and mouse sepsis model in vivo. Thio-Cl-IB-MECA exhibited an effective anti-inflammatory activity. The expression of pro-inflammatory biomarkers including inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), and tumor necrosis factor (TNF-α) was suppressed by the treatment of thio-Cl-IB-MECA in the protein and mRNA levels in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells. Further examination revealed that thio-Cl-IB-MECA inhibited LPS-induced phosphatidylinositol 3-kinase (PI3 kinase)/Akt activation, NF-kB binding activity, and β-catenin expression. In addition, in in vivo LPS-induced mouse endotoxemia model, thio-Cl-IB-MECA exerted the increase of survival rate compared to vehicle-treated mouse. The analysis of the protein levels of iNOS, IL-1β, and TNF-α was also suppressed by the compound-treated groups in lung tissues. These results suggest that thio-Cl-IB-MECA might have an anti-inflammatory activity through the inhibition of pro-inflammatory cytokine expression by modulating PI3K/Akt and NF-κB signaling pathways. © 2011 Elsevier GmbH.
DOI
10.1016/j.imbio.2011.03.008
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약학대학 > 약학과 > Journal papers
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