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Adenosine signalling mediates the anti-inflammatory effects of the COX-2 inhibitor nimesulide.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2016 Jul 15; Vol. 112, pp. 72-81. Date of Electronic Publication: 2016 May 14. - Publication Year :
- 2016
-
Abstract
- Extracellular adenosine formation from ATP is controlled by ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase/CD39) and ecto-5'-nucleotidase (e-5NT/CD73); the latter converts AMP to adenosine and inorganic phosphate, representing the rate limiting step controlling the ratio between extracellular ATP and adenosine. Evidence that cellular expression and activity of CD39 and CD73 may be subject to changes under pathophysiological conditions has identified this pathway as an endogenous modulator in several diseases and was shown to be involved in the molecular mechanism of drugs, such as methotrexate, salicylates , interferon-β. We evaluated whether CD73/adenosine/A2A signalling pathway is involved in nimesulide anti-inflammatory effect, in vivo and in vitro. We found that the adenosine A2A agonist, 4-[2-[[6-amino-9-(N-ethyl-β-d-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (CGS21680, 2mg/kg ip.), inhibited carrageenan-induced rat paw oedema and the effect was reversed by co-administration of the A2A antagonist -(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM241385; 3mg/kg i.p.). Nimesulide (5mg/kg i.p.) anti-inflammatory effect was inhibited by pre-treatment with ZM241385 (3mg/kg i.p.) and by local administration of the CD73 inhibitor, adenosine 5'-(α,β-methylene)diphosphate (APCP; 400μg/paw). Furthermore, we found increased activity of 5'-nucleotidase/CD73 in paws and plasma of nimesulide treated rats, 4h following oedema induction. In vitro, the inhibitory effect of nimesulide on nitrite and prostaglandin E2 production by lipopolysaccharide-activated J774 cell line was reversed by ZM241385 and APCP. Furthermore, nimesulide increased CD73 activity in J774 macrophages while it did not inhibit nitrite accumulation by lipopolysaccharide-activated SiRNA CD73 silenced J774 macrophages. Our data demonstrate that the anti-inflammatory effect of nimesulide in part is mediated by CD73-derived adenosine acting on A2A receptors.<br /> (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Subjects :
- 5'-Nucleotidase antagonists & inhibitors
5'-Nucleotidase blood
5'-Nucleotidase metabolism
Animals
Anti-Inflammatory Agents therapeutic use
Cell Line
Cyclooxygenase 2 Inhibitors administration & dosage
Dinoprostone blood
Edema drug therapy
Edema immunology
Edema metabolism
Macrophages drug effects
Macrophages immunology
Male
Rats, Wistar
Receptor, Adenosine A2A metabolism
Sulfonamides administration & dosage
Adenosine metabolism
Anti-Inflammatory Agents pharmacology
Cyclooxygenase 2 Inhibitors pharmacology
Signal Transduction drug effects
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 112
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 27188793
- Full Text :
- https://doi.org/10.1016/j.bcp.2016.05.006