RT Journal Article SR Electronic T1 Effect of A2B Adenosine Receptor Gene Ablation on Adenosine-Dependent Regulation of Proinflammatory Cytokines JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 694 OP 700 DO 10.1124/jpet.107.131540 VO 324 IS 2 A1 Sergey Ryzhov A1 Rinat Zaynagetdinov A1 Anna E. Goldstein A1 Sergey V. Novitskiy A1 Michael R. Blackburn A1 Italo Biaggioni A1 Igor Feoktistov YR 2008 UL http://jpet.aspetjournals.org/content/324/2/694.abstract AB Pharmacological studies suggest that A2B adenosine receptors mediate proinflammatory effects of adenosine. This concept was recently challenged by the finding that A2B adenosine receptor knockout (A2BKO) mice had moderate inflammation due to elevated basal plasma tumor necrosis factor (TNF)-α and an exaggerated response to lipopolysaccharide (LPS) challenge. However, it is unclear whether this phenomenon actually reflects the loss of putative taming of proinflammatory cytokine production via activation of A2B receptors by endogenous adenosine. In this report, we examined adenosine receptor-dependent regulation of interleukin (IL)-6 and TNF-α blood plasma levels in A2BKO and wild-type mice in vivo and their release from peritoneal macrophages ex vivo. Stimulation of adenosine receptors with 5′-N-ethylcarboxamidoadenosine (NECA) up-regulated IL-6 and suppressed LPS-induced TNF-α in wild-type mice. The selective A2B antagonists 3-isobutyl-8-pyrrolidinoxanthine and 8-[4-[((4-cyanophenyl)carbamoylmethyl)oxy]phenyl]-1,3-di(n-propyl)xanthine (MRS 1754) inhibited NECA-induced IL-6 release but not the suppression of LPS-induced TNF-α secretion from macrophages. Genetic ablation of A2B receptors abrogated NECA-induced increases in IL-6 release from mouse peritoneal macrophages and dramatically reduced the ability of NECA to raise IL-6 plasma levels in vivo. In contrast, the absence of A2B adenosine receptors did not affect NECA-induced suppression of LPS-activated TNF-α release in macrophages, nor did it reduce the ability of NECA to suppress LPS-induced increase in TNF-α plasma levels in vivo. Thus, our results indicate that stimulation of A2B receptors up-regulates the proinflammatory cytokine IL-6 and argue against the recently suggested anti-inflammatory role of A2B receptors in suppression of LPS-stimulated TNF-α production by adenosine. The American Society for Pharmacology and Experimental Therapeutics