title: Inhibition of TNF-alpha expression by adenosine: role of A3 adenosine receptors.
abstract: Adenosine agonists inhibit TNF-alpha production in macrophage and monocytes, but the mechanism is unknown. Therefore, we studied the human macrophage cell line U937 to determine the adenosine receptor subtypes responsible and the intracellular signaling mechanisms involved. The A1/A3 agonist N6-(4-amino-3-iodobenzyl)adenosine (I-ABA) decreased LPS-stimulated TNF-alpha protein production by 79 +/- 5% (p = 0.003). The mechanism was pretranslational, as adenosine receptor stimulation caused a marked decrease in TNF-alpha mRNA. IL-1 beta, IL-6, and IL-8 mRNA were not changed by adenosine agonists. The rank order of agonists as TNF-alpha inhibitors suggested that the A3 receptor might be involved (N6-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-beta-D-ribofuranosyl] adenosine > 2-chloroadenosine > or = I-ABA > N6 benzyl 5'-N-ethylcarboxamidoadenosine (NECA) > NECA > CGS21680 > N6-cyclohexyladenosine), and this was supported by the fact that a mixed A1/A3 antagonist (xanthine amine congener) reversed the effect, whereas A1-specific (1,3-dipropyl-8-cyclopentylxanthine) and A2-specific (3,7-dimethyl-1-propargylxanthine) antagonists did not. Receptor signaling did not involve cAMP or protein kinase A, nor did it alter the activation and binding characteristics of the transcription factor NF-kappa B. However, the composition of the AP-1 transcription complex was altered by I-ABA. These data suggest that stimulation of the A3 adenosine receptor can alter the cytokine milieu by decreasing TNF-alpha. Adenosine agonists or adenosine regulating agents have potential therapeutic uses in acute and chronic inflammatory diseases.
authors.affiliation: Gensia, Inc., San Diego, CA 92121, USA.
authors.forename: F G
authors.initials: FG
authors.lastname: Sajjadi
authors.forename: K
authors.initials: K
authors.lastname: Takabayashi
authors.forename: A C
authors.initials: AC
authors.lastname: Foster
authors.forename: R C
authors.initials: RC
authors.lastname: Domingo
authors.forename: G S
authors.initials: GS
authors.lastname: Firestein
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011494:Protein Kinases / Q000502:physiology; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger / Q000187:drug effects; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
chemical_list: D016328:NF-kappa B; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D018047:Receptors, Purinergic P1; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D011494:Protein Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases; D000241:Adenosine