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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2685-2695. Prepublished online as a Blood First Edition Paper on May 24, 2007; DOI 10.1182/blood-2007-01-065870. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-01-065870v1 110/7/2685    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Csóka, B. Articles by Haskó, G. Search for Related Content PubMed PubMed Citation Articles by Csóka, B. Articles by Haskó, G. Related Collections Immunobiology Phagocytes Signal Transduction Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES A2A adenosine receptors and C/EBPß are crucially required for IL-10 production by macrophages exposed to Escherichia coli Balázs Csóka1, Zoltán H. Németh1, László Virág2, Pál Gergely2, S. Joseph Leibovich3, Pál Pacher4, Chun-Xiao Sun5, Michael R. Blackburn5, E. Sylvester Vizi6, Edwin A. Deitch1, and György Haskó1,6 1 Department of Surgery, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, Newark; 2 Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; 3 Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, Newark; 4 National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD; 5 Department of Biochemistry and Molecular Biology, University of Texas–Houston Medical School; 6 Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary We recently showed that A2A adenosine receptor activation by endogenous adenosine contributes to interleukin-10 (IL-10) production in polymicrobial sepsis. Here we investigated the molecular mechanisms underpinning this interaction between adenosine receptor signaling and infection by exposing macrophages to Escherichia coli. We demonstrated using receptor knockout mice that A2A receptor activation is critically required for the stimulatory effect of adenosine on IL-10 production by E coli–challenged macrophages, whereas A2B receptors have a minor role. The stimulatory effect of adenosine on E coli–induced IL-10 production did not require toll-like receptor 4 (TLR4) or MyD88, but was blocked by p38 inhibition. Using shRNA we demonstrated that TRAF6 impairs the potentiating effect of adenosine. Measuring IL-10 mRNA abundance and transfection with an IL-10 promoter-luciferase construct indicated that E coli and adenosine synergistically activate IL-10 transcription. Sequential deletion analysis and site-directed mutagenesis of the IL-10 promoter revealed that a region harboring C/EBP binding elements was responsible for the stimulatory effect of adenosine on E coli–induced IL-10 promoter activity. Adenosine augmented E coli–induced nuclear accumulation and DNA binding of C/EBPß. C/EBPß-deficient macrophages failed to produce IL-10 in response to adenosine and E coli. Our results suggest that the A2A receptor–C/EBPß axis is critical for IL-10 production after bacterial infection. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. C. Loram, J. A. Harrison, E. M. Sloane, M. R. Hutchinson, P. Sholar, F. R. Taylor, D. Berkelhammer, B. D. Coats, S. Poole, E. D. Milligan, et al. Enduring Reversal of Neuropathic Pain by a Single Intrathecal Injection of Adenosine 2A Receptor Agonists: A Novel Therapy for Neuropathic Pain J. Neurosci., November 4, 2009; 29(44): 14015 - 14025. [Abstract] [Full Text] [PDF] J. Skupsky, A.-H. Zhang, and D. W. Scott Unraveling the Danger Signal Necessary for the Immune Response to Therapeutic Factor VIII. Blood (ASH Annual Meeting Abstracts), November 16, 2008; 112(11): 1220 - 1220. [Abstract] 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] G. Hasko and P. Pacher A2A receptors in inflammation and injury: lessons learned from transgenic animals J. Leukoc. Biol., March 1, 2008; 83(3): 447 - 455. [Abstract] [Full Text] [PDF] S. Ryzhov, R. Zaynagetdinov, A. E. Goldstein, S. V. Novitskiy, M. R. Blackburn, I. Biaggioni, and I. Feoktistov Effect of A2B Adenosine Receptor Gene Ablation on Adenosine-Dependent Regulation of Proinflammatory Cytokines J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 694 - 700. [Abstract] [Full Text] [PDF]

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