title: Differential modulation of lipopolysaccharide-induced expression of inflammatory genes in equine monocytes through activation of adenosine A2A receptors.
abstract: Adenosine is an endogenous nucleoside that has potent receptor-mediated immunomodulatory effects on macrophage/monocyte function. In this study, we determined the effects of an adenosine A(2A) receptor agonist, ATL313, on the expression of mRNAs for four pro-inflammatory mediators, IL-1beta, IL-8, COX-2, and TNF-alpha, and the mRNA and protein for the anti-inflammatory cytokine, IL-10 in equine monocytes incubated with lipopolysaccharide (LPS). The results indicate that ATL313 significantly reduces LPS-induced expression of COX-2 and TNF-alpha, enhances the expression of IL-10 and IL-8, but does not alter the expression of IL-1beta. These effects of ATL313 were reversed by co-incubation with the selective adenosine A(2A) antagonist ZM241385, and were mimicked by the cAMP analogue dibutyryl cAMP. These differential effects of adenosine A(2A) receptor activation were in contrast to those obtained using the P38 MAPK inhibitor, SB203580, which nearly abolished all LPS-induced changes in mRNA expression as well as the production of TNF-alpha protein. These findings, which indicate that adenosine A(2A) receptor activation modulates the transcription of several, but not all, pro-inflammatory mediators and exerts a synergistic effect on the induction of at least one anti-inflammatory cytokine, suggest that selective adenosine A(2A) agonists may reduce the early pro-inflammatory effects of endotoxemia in horses.
authors.affiliation: Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
authors.forename: Wan-chun
authors.initials: WC
authors.lastname: Sun
authors.forename: James N
authors.initials: JN
authors.lastname: Moore
authors.forename: David J
authors.initials: DJ
authors.lastname: Hurley
authors.forename: Michel L
authors.initials: ML
authors.lastname: Vandenplas
authors.forename: Barbara
authors.initials: B
authors.lastname: Fortes
authors.forename: Robert
authors.initials: R
authors.lastname: Thompson
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
mesh_terms: D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D001483:Base Sequence; D003994:Bucladesine / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006736:Horses / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
chemical_list: C510376:ATL 313; D058908:Adenosine A2 Receptor Agonists; D016207:Cytokines; D017931:DNA Primers; D007093:Imidazoles; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010880:Piperidines; D011725:Pyridines; D043705:Receptor, Adenosine A2A; D016753:Interleukin-10; D003994:Bucladesine; D051546:Cyclooxygenase 2; C093642:SB 203580