Effect of A2B adenosine receptor gene ablation on adenosine-dependent regulation of proinflammatory cytokines.
Pharmacological studies suggest that A(2B) adenosine receptors mediate proinflammatory effects of adenosine. This concept was recently challenged by the finding that A(2B) adenosine receptor knockout (A(2B)KO) mice had moderate inflammation due to elevated basal plasma tumor necrosis factor (TNF)-alpha 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 A(2B) receptors by endogenous adenosine. In this report, we examined adenosine receptor-dependent regulation of interleukin (IL)-6 and TNF-alpha blood plasma levels in A(2B)KO 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-alpha in wild-type mice. The selective A(2B) 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-alpha secretion from macrophages. Genetic ablation of A(2B) 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 A(2B) adenosine receptors did not affect NECA-induced suppression of LPS-activated TNF-alpha release in macrophages, nor did it reduce the ability of NECA to suppress LPS-induced increase in TNF-alpha plasma levels in vivo. Thus, our results indicate that stimulation of A(2B) receptors up-regulates the proinflammatory cytokine IL-6 and argue against the recently suggested anti-inflammatory role of A(2B) receptors in suppression of LPS-stimulated TNF-alpha production by adenosine.
Ryzhov
Sergey
S
Divisions of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Zaynagetdinov
Rinat
R
Goldstein
Anna E
AE
Novitskiy
Sergey V
SV
Blackburn
Michael R
MR
Biaggioni
Italo
I
Feoktistov
Igor
I
D000241:Adenosine / Q000494:pharmacology / Q000502:physiology*; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043704:Receptor, Adenosine A2B / Q000096:biosynthesis* / Q000235:genetics*
D058917:Adenosine A2 Receptor Antagonists; D016207:Cytokines; D043704:Receptor, Adenosine A2B; D000241:Adenosine