TY - JOUR T1 - Effect of A<sub>2B</sub> Adenosine Receptor Gene Ablation on Adenosine-Dependent Regulation of Proinflammatory Cytokines JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 694 LP - 700 DO - 10.1124/jpet.107.131540 VL - 324 IS - 2 AU - Sergey Ryzhov AU - Rinat Zaynagetdinov AU - Anna E. Goldstein AU - Sergey V. Novitskiy AU - Michael R. Blackburn AU - Italo Biaggioni AU - Igor Feoktistov Y1 - 2008/02/01 UR - http://jpet.aspetjournals.org/content/324/2/694.abstract N2 - 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 ER -