QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.131540v1 324/2/694    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Ryzhov, S. Articles by Feoktistov, I. PubMed PubMed Citation Articles by Ryzhov, S. Articles by Feoktistov, I.

INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Effect of A_2B Adenosine Receptor Gene Ablation on Adenosine-Dependent Regulation of Proinflammatory Cytokines

Divisions of Cardiovascular Medicine (S.R., R.Z., I.F.), Hematology/Oncology (S.V.N.), and Clinical Pharmacology (A.E.G., I.B.), Departments of Medicine (S.R., R.Z., S.V.N., I.B., I.F.) and Pharmacology (A.E.G., I.B., I.F.), Vanderbilt University, Nashville, Tennessee; and Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, Texas (M.R.B.)

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_2BKO) mice had moderate inflammation due to elevated basal plasma tumor necrosis factor (TNF)- 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- 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) up-regulated IL-6 and suppressed LPS-induced TNF- 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- 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 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- production by adenosine.

Address correspondence to: Dr. Igor Feoktistov, 360 PRB, Vanderbilt University, 2220 Pierce Ave., Nashville, TN 37232-6300. E-mail: igor.feoktistov{at}vanderbilt.edu

This article has been cited by other articles:

				S. Ryzhov, R. Zaynagetdinov, A. E. Goldstein, S. V. Novitskiy, M. M. Dikov, M. R. Blackburn, I. Biaggioni, and I. Feoktistov Effect of A2B Adenosine Receptor Gene Ablation on Proinflammatory Adenosine Signaling in Mast Cells J. Immunol., June 1, 2008; 180(11): 7212 - 7220. [Abstract] [Full Text] [PDF]

				D. Yang, M. Koupenova, D. J. McCrann, K. J. Kopeikina, H. M. Kagan, B. M. Schreiber, and K. Ravid The A2b adenosine receptor protects against vascular injury PNAS, January 15, 2008; 105(2): 792 - 796. [Abstract] [Full Text] [PDF]