title: The A2A receptor mediates an endogenous regulatory pathway of cytokine expression in THP-1 cells.
abstract: Adenosine is an endogenous nucleoside that regulates numerous cellular functions including inflammation. Adenosine acts via cell-surface receptors subtyped as A1, A2A, A2B, and A3. The A2A receptor (A2AR) has been linked to anti-inflammatory effects of adenosine. Furthermore, microarray analysis revealed increased A2AR mRNA in lipopolysaccharide (LPS)-stimulated monocytes. We hypothesized that endogenous adenosine inhibited LPS-mediated tumor necrosis factor (TNF) production via A2AR stimulation. Using THP-1 cells, our results demonstrated that LPS increased expression of cellular A2AR and adenosine. A2AR agonism with 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine (CGS 21680) after LPS decreased TNF production in a dose- and time-dependent manner, whereas A2AR antagonism significantly increased TNF and blocked the inhibitory effect of CGS 21680. This inhibitory pathway involved A2AR stimulation of cyclic adenosine monophosphate (cAMP) to activate protein kinase A, resulting in phosphorylation of cAMP response element-binding protein (CREB). Phospho-CREB had been shown to inhibit nuclear factor-kappaB transcriptional activity, as was observed with CGS 21680 treatment. Thus, following immune activation with LPS, endogenous adenosine mediates a negative feedback pathway to modulate cytokine expression in THP-1 cells.
authors.affiliation: Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
authors.forename: Khaled
authors.initials: K
authors.lastname: Bshesh
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.forename: Donn
authors.initials: D
authors.lastname: Spight
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
authors.forename: Igor
authors.initials: I
authors.lastname: Feokistov
authors.forename: Alvin
authors.initials: A
authors.lastname: Denenberg
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Shanley
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger / Q000096:biosynthesis; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010627:Phenethylamines; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine