Journal
JOURNAL OF IMMUNOLOGY
Volume 185, Issue 1, Pages 542-550Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0901295
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Funding
- National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism [R01GM66189]
- Hungarian Research Fund [CK 78275]
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Despite intensive research, efforts to reduce the mortality of septic patients have failed. Adenosine is a potent extracellular signaling molecule, and its levels are elevated in sepsis. Adenosine signals through G-protein-coupled receptors and can regulate the host's response to sepsis. In this study, we studied the role of A(2B) adenosine receptors in regulating the mortality and inflammatory response of mice following polymicrobial sepsis. Genetic deficiency of A(2B) receptors increased the mortality of mice suffering from cecal ligation and puncture-induced sepsis. The increased mortality of A(2B) knockout mice was associated with increased levels of inflammatory cytokines and chemokines and augmented NF-kappa B and p38 activation in the spleen, heart, and plasma in comparison with wild-type animals. In addition, A(2B) receptor knockout mice showed increased splenic apoptosis and phosphatase and tensin homolog activation and decreased Akt activation. Experiments using bone-marrow chimeras revealed that it is the lack of A(2B) receptors on nonhematopoietic cells that is primarily responsible for the increased inflammation of septic A(2B) receptor-deficient mice. These results indicate that A(2B) receptor activation may offer a new therapeutic approach for the management of sepsis. The Journal of Immunology, 2010, 185: 542-550.
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