ADENOSINE RECEPTOR AGONISTS DIFFERENTIALLY REGULATE IL-10, TNF-ALPHA AND NITRIC-OXIDE PRODUCTION IN RAW-264.7 MACROPHAGES AND IN ENDOTOXEMIC MICE

Adenosine released into the extracellular space by immunologic and non immunologic stimuli has been shown to regulate various immune function s, In this study we report that i.p. pretreatment of mice with CGS-216 80 HCl (CGS), a selective agonist of A(2) 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-al pha, 2-Chloro-N-6-cyclopentyladenosine (CCPA), an agonist of A(1) aden osine receptors, at 0.5 mg/kg diminished LPS-induced plasma TNF-alpha concentrations, but enhanced LPS-induced IL-10 levels only at the high est dose used (2 mg/kg), The specific A(3) adenosine receptor agonist 9H-purin-9-yl]-N-methyl-beta-D-ribofuranuronamide, at 0.2 and 0.5 mg/k g potentiated LPS-stimulated IL-10 production and inhibited LPS-induce d TNF-alpha production, LPS-induced plasma nitrite and nitrate levels (the breakdown products of nitric oxide (NO)) were suppressed by CGS a nd CCPA. In the RAW 264.7 macrophage cell line, pretreatment of the ce lls with both CGS and CCPA inhibited LPS-induced IL-10, TNF-alpha, and NO production, each in a concentration-dependent manner. The inhibito ry 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-kappa B in these cells, These results demonstrate that adenosi ne receptor stimulation differentially modulates the LPS-induced produ ction of IL-10, TNF-alpha, and NO in vitro and in vivo. The increase i n LPS-induced IL-10 production and suppression of LPS-induced TNF-alph a and NO production caused by adenosine receptor activation may explai n some of the immunomodulatory actions of adenosine released in excess during inflammatory and/or ischemic insult.