TY - JOUR
T1 - A2B Adenosine Receptor Gene Deletion Attenuates Murine Colitis
AU - Kolachala, Vasantha L.
AU - Vijay-Kumar, Matam
AU - Dalmasso, Guillaiume
AU - Yang, Dan
AU - Linden, Joel
AU - Wang, Lixin
AU - Gewirtz, Andrew
AU - Ravid, Katya
AU - Merlin, Didier
AU - Sitaraman, Shanthi V.
PY - 2008/9
Y1 - 2008/9
N2 - Background & Aims: The A2B adenosine receptor (A2BAR) is the predominant adenosine receptor expressed in the colonic epithelia. We have previously shown that A2BAR mRNA and protein levels are up-regulated during colitis. In this study, we addressed the role of the A2BAR in the development of murine colitis and the potential mechanism underlying its effects. Methods: Dextran sodium sulfate (DSS), 2,4,6-trinitrobenzene sulfonic acid (TNBS), and Salmonella typhimurium were used to induce colitis in A2BAR-null mice (A2BAR-/-). Colitis was determined using established clinical and histologic scoring. Keratinocyte-derived chemokine (KC) measurements were performed using an enzyme-linked immunosorbent assay. Results: Colonic inflammation induced by DSS, TNBS, or S typhimurium was attenuated in A2BAR-/- compared with their wild-type counterparts. Clinical features, histologic score, and myeloperoxidase activity were significantly decreased in A2BAR-/- mice. However, A2BAR-/- showed increased susceptibility to systemic Salmonella infection. Tissue levels of the neutrophil chemokine, KC was decreased in colitic A2BAR-/- mice. In addition, flagellin-induced KC levels were attenuated in A2BAR-/- mice. Neutrophil chemotaxis in response to exogenous interleukin-8 was preserved in A2BAR-/- mice, suggesting intact neutrophil migration in response to appropriate stimuli. Conclusions: These data demonstrate, for the first time, that the A2BAR plays a proinflammatory role in colitis. A2B receptor antagonism may be an effective treatment for acute inflammatory intestinal diseases such as acute flare of inflammatory bowel disease.
AB - Background & Aims: The A2B adenosine receptor (A2BAR) is the predominant adenosine receptor expressed in the colonic epithelia. We have previously shown that A2BAR mRNA and protein levels are up-regulated during colitis. In this study, we addressed the role of the A2BAR in the development of murine colitis and the potential mechanism underlying its effects. Methods: Dextran sodium sulfate (DSS), 2,4,6-trinitrobenzene sulfonic acid (TNBS), and Salmonella typhimurium were used to induce colitis in A2BAR-null mice (A2BAR-/-). Colitis was determined using established clinical and histologic scoring. Keratinocyte-derived chemokine (KC) measurements were performed using an enzyme-linked immunosorbent assay. Results: Colonic inflammation induced by DSS, TNBS, or S typhimurium was attenuated in A2BAR-/- compared with their wild-type counterparts. Clinical features, histologic score, and myeloperoxidase activity were significantly decreased in A2BAR-/- mice. However, A2BAR-/- showed increased susceptibility to systemic Salmonella infection. Tissue levels of the neutrophil chemokine, KC was decreased in colitic A2BAR-/- mice. In addition, flagellin-induced KC levels were attenuated in A2BAR-/- mice. Neutrophil chemotaxis in response to exogenous interleukin-8 was preserved in A2BAR-/- mice, suggesting intact neutrophil migration in response to appropriate stimuli. Conclusions: These data demonstrate, for the first time, that the A2BAR plays a proinflammatory role in colitis. A2B receptor antagonism may be an effective treatment for acute inflammatory intestinal diseases such as acute flare of inflammatory bowel disease.
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U2 - 10.1053/j.gastro.2008.05.049
DO - 10.1053/j.gastro.2008.05.049
M3 - Article
C2 - 18601927
AN - SCOPUS:51049083079
SN - 0016-5085
VL - 135
SP - 861
EP - 870
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -