Received for publication September 12, 2007.
Revised October 19, 2007.
Accepted for publication October 25, 2007.

Effect of A_2B adenosine receptor gene ablation on adenosine-dependent regulation of pro-inflammatory cytokines

Abstract

Pharmacological studies suggest that A_2B adenosine receptors mediate pro-inflammatory effects of adenosine. Recently, this concept has been challenged by the finding that A_2B knockout (A_2BKO) mice have moderate inflammation due to elevated basal plasma tumor necrosis factor-alpha (TNF-) and an exaggerated response to lypopolysacharide (LPS) challenge. However, it is unclear if this phenomenon actually reflects the loss of putative taming of pro-inflammatory cytokine production via activation of A_2B receptors by endogenous adenosine. Here, we studied adenosine receptor-dependent regulation of interleukin (IL)-6 and TNF- blood plasma levels in A_2BKO and wild-type mice in vivo and their release from peritoneal macrophages ex vivo. Stimulation of adenosine receptors with 5'-N-ethylcarboxamidoadenosine (NECA) upregulated IL-6 and suppressed LPS-induced TNF- in wild-type mice. The selective A_2B antagonists IPDX and MRS 1754 inhibited NECA-induced IL-6 release but not the suppression of LPS-induced TNF- 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- release in macrophages, nor did it reduce the ability of NECA to suppress LPS-induced increase in TNF- plasma levels in vivo. Thus, our results indicate that stimulation of A_2B receptors upregulates the pro-inflammatory cytokine IL-6, and argue against the recently suggested anti-inflammatory role of A_2B receptors in suppression of LPS-stimulated TNF- production by adenosine.

Key words: adenosine, inflammation, interleukin-6, macrophage, receptors purinergic, P1, tumor necrosis factor alpha

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