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* Institute for Medical Microbiology and Hygiene, University Hospital, Tübingen, Germany;
Mucosal Inflammation Program, University of Colorado Health Sciences Center, Aurora, CO 80045;
Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany; and
Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Science Center, Aurora, CO 80045
Inflammatory diseases influence tissue metabolism, significantly altering the profile of extracellular adenine nucleotides. A number of studies have suggested that adenosine (Ado) may function as an endogenously generated anti-inflammatory molecule. Given the central role of intestinal epithelial cells to the development of colitis, we hypothesized that specific Ado receptors would contribute to disease resolution in mucosal inflammation as modeled by dextran sodium sulfate (DSS) colitis. Initial profiling studies revealed that murine intestinal epithelial cells express predominantly the Ado A2B receptor (AA2BR) and to a lesser extent AA2AR. Guided by these results, we examined the contribution of AA2BR to colitis. Initial studies indicated that the severity of colitis was increased in Aa2br–/– mice relative to Aa2br+/+ controls, as reflected by increased weight loss, colonic shortening, and disease activity indices. Likewise, enteral administration of the selective AA2BR inhibitor PSB1115 to Aa2br+/+ mice resulted in a similar increase in severity of DSS colitis. Cytokine profiling of colonic tissue revealed specific deficiencies in IL-10 in Aa2br–/– mice relative to controls. Extensions of these findings in cultured human intestinal epithelial cells revealed that stable Ado analogs induce IL-10 mRNA and protein and that such increases can be blocked with PSB1115. Taken together, these studies indicate a central regulatory role for AA2BR-modulated IL-10 in the acute inflammatory phase of DSS colitis, thereby implicating AA2BR as an endogenously protective molecule expressed on intestinal epithelial cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants DK50189, DE016191, and HL60569 and by a grant from the Crohn’s and Colitis Foundation of America.
2 Address correspondence and reprint requests to Dr. Holger K. Eltzschig or Dr. Sean P. Colgan, Mucosal Inflammation Program, 12700 East 19th Avenue, Aurora, CO 80045. E-mail addresses: holger.eltzschig{at}uchsc.edu or sean.colgan{at}uchsc.edu
3 Abbreviations used in this paper: IBD, inflammatory bowel disease; AA2AR, adenosine A2A receptor; AA2BR, adenosine A2B receptor; AA3R, adenosine A3 receptor; Ado, adenosine; DSS, dextran sodium sulfate; NECA, N-ethyl-carbamido-adenosine.
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