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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.
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Submitted January 3, 2007
Accepted May 22, 2007
A2A adenosine receptors and C/EBP are crucially required for IL-10 production by macrophages exposed to E. coli
Balazs Csoka, Zoltan H Nemeth, Laszlo Virag, Pal Gergely, S. Joseph Leibovich, Pal Pacher, Chun-Xiao Sun, Michael R. Blackburn, E. Sylvester Vizi, Edwin A Deitch, and Gyorgy Hasko*
Department of Surgery, UMDNJ-New Jersey Medical School, Newark, NJ
Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
Department of Cell Biology and Molecular Medicine, UMDNJ-New Jersey Medical School, Newark, NJ
National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD
Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
* Corresponding author; email: haskoge{at}umdnj.edu.
We recently showed that A2A adenosine receptor activation by endogenous adenosine contributes to 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 E. 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 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/EBP . C/EBP deficient macrophages failed to produce IL-10 in response to adenosine and E. coli. Our results suggest that the A2A receptor-C/EBP axis is critical for IL-10 production following bacterial infection.
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