Contribution of Adenosine A2B Receptors to Inflammatory Parameters of Experimental Colitis
| Autor: | Julia-Stefanie Frick, Louise E. Glover, Holger K. Eltzschig, Christopher F. MacManus, Sean P. Colgan, Melanie Scully |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Immunology Biology Pharmacology Receptor Adenosine A2B Article Mice Intestinal mucosa Adenine nucleotide Extracellular medicine Animals Humans Immunology and Allergy Intestinal Mucosa Colitis Receptor Mice Knockout Dextran Sulfate medicine.disease Adenosine Interleukin-10 Disease Models Animal Interleukin 10 Gene Expression Regulation Caco-2 Female Disease Susceptibility Caco-2 Cells medicine.drug |
| Zdroj: | The Journal of Immunology. 182:4957-4964 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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