Adenosine Receptor Agonists Differentially Regulate IL-10, TNF-α, and Nitric Oxide Production in RAW 264.7 Macrophages and in Endotoxemic Mice

György Haskó, Csaba Szabó, Zoltán H. Németh, Vladimir Kvetan, Stephen Mc Carthy Pastores, E. Sylvester Vizi

Research output: Contribution to journalArticle

417 Scopus citations

Abstract

Adenosine released into the extracellular space by immunologic and nonimmunologic stimuli has been shown to regulate various immune functions. In this study we report that i.p. pretreatment of mice with CGS-21680 HCl (CGS), a selective agonist of A2 adenosine receptors, at 0.2 to 2 mg/kg caused an augmentation of plasma IL-10 levels induced by i.p. injection of LPS, but decreased plasma levels of LPS-induced TNF-α. 2-Chloro-N6-cyclopentyladenosine (CCPA), an agonist of A1 adenosine receptors, at 0.5 mg/kg diminished LPS-induced plasma TNF-α concentrations, but enhanced LPS-induced IL-10 levels only at the highest dose used (2 mg/kg). The specific A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-D- ribofuranuronamide, at 0.2 and 0.5 mg/kg potentiated LPS-stimulated IL-10 production and inhibited LPS-induced TNF-α production. LPS-induced plasma nitrite and nitrate levels (the breakdown products of nitric oxide (NO)) were suppressed by CGS and CCPA. In the RAW 264.7 macrophage cell line, pretreatment of the cells with both CGS and CCPA inhibited LPS-induced IL-10, TNF-α, and NO production, each in a concentration-dependent manner. The inhibitory effect of these drugs on cytokine and NO production was associated with improved mitochondrial respiration. Neither CGS nor CCPA affected the LPS-induced nuclear translocation of transcription factor nuclear factor-κB in these cells. These results demonstrate that adenosine receptor stimulation differentially modulates the LPS-induced production of IL-10, TNF-α, and NO in vitro and in vivo. The increase in LPS-induced IL-10 production and suppression of LPS-induced TNF-α and NO production caused by adenosine receptor activation may explain some of the immunomodulatory actions of adenosine released in excess during inflammatory and/or ischemic insult.

Original languageEnglish (US)
Pages (from-to)4634-4640
Number of pages7
JournalJournal of Immunology
Volume157
Issue number10
StatePublished - Nov 15 1996

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Haskó, G., Szabó, C., Németh, Z. H., Kvetan, V., Pastores, S. M. C., & Vizi, E. S. (1996). Adenosine Receptor Agonists Differentially Regulate IL-10, TNF-α, and Nitric Oxide Production in RAW 264.7 Macrophages and in Endotoxemic Mice. Journal of Immunology, 157(10), 4634-4640.