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Blockade of adenosine A2B receptors ameliorates murine colitis
Vl Kolachala1, Bk Ruble, M Vijay-Kumar
1Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
Background And Purpose:
The adenosine 2B (A2B) receptor is the predominant adenosine receptor expressed in the colon. Acting through the A2B receptor, adenosine mediates chloride secretion, as well as fibronectin and interleukin (IL)-6 synthesis and secretion in intestinal epithelial cells. A2B receptor mRNA and protein expression are increased during human and murine colitis. However, the effect of the A2B receptor in the activation of the intestinal inflammatory response is not known. In this study, we examined the effect of A2B receptor antagonism on murine colitis.
Experimental Approach:
Dextran sodium sulphate (DSS)-treated mice and piroxicam-treated IL-10-/- mice were used as animal models of colitis. The A2B receptor-selective antagonist, ATL-801, was given in the diet.
Key Results:
Mice fed ATL-801 along with DSS showed a significantly lower extent and severity of colitis than mice treated with DSS alone, as shown by reduced clinical symptoms, histological scores, IL-6 levels and proliferation indices. The administration of ATL-801 prevented weight loss, suppressed the inflammatory infiltrate into colonic mucosa and decreased epithelial hyperplasia in piroxicam-treated IL-10-/- mice. IL-6 and keratinocyte-derived chemokine (KC) concentrations in the supernatants of colonic organ cultures from colitic mice were significantly reduced by ATL-801 administration.
Conclusions And Implications:
Taken together, these data demonstrate that the intestinal epithelial A2B receptor is an important mediator of pro-inflammatory responses in the intestine and that A2B receptor blockade may be an effective therapeutic strategy to treat inflammatory bowel disease.
Insights
Blocking the adenosine 2B (A2B) receptor reduces inflammation in colitis models. A2B receptor antagonism effectively treats inflammatory bowel disease by reducing key inflammatory markers.
Area of Science:
- Gastroenterology
- Immunology
- Pharmacology
Background:
- The adenosine 2B (A2B) receptor is highly expressed in the colon and mediates inflammatory responses.
- A2B receptor expression is elevated during colitis, but its role in intestinal inflammation is unclear.
Purpose of the Study:
- To investigate the therapeutic potential of A2B receptor antagonism in murine colitis models.
Main Methods:
- Two models of colitis were used: dextran sodium sulphate (DSS)-induced and piroxicam-induced in IL-10-/- mice.
- Mice received the selective A2B receptor antagonist ATL-801 in their diet.
Main Results:
- ATL-801 treatment significantly reduced colitis severity, clinical symptoms, and histological damage in DSS-treated mice.
- ATL-801 prevented weight loss, suppressed inflammation, and reduced epithelial hyperplasia in piroxicam-treated IL-10-/- mice.
- Key inflammatory mediators, including IL-6 and KC, were significantly decreased by ATL-801.
Conclusions:
- The intestinal epithelial A2B receptor plays a crucial role in mediating pro-inflammatory responses in the gut.
- A2B receptor blockade represents a promising therapeutic strategy for inflammatory bowel diseases.
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