A2B adenosine receptor gene deletion attenuates murine colitis.
OBJECTIVE
The A(2B) adenosine receptor (A(2B)AR) is the predominant adenosine receptor expressed in the colonic epithelia. We have previously shown that A(2B)AR mRNA and protein levels are up-regulated during colitis. In this study, we addressed the role of the A(2B)AR 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 A(2B)AR-null mice (A(2B)AR(-/-)). 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 A(2B)AR(-/-) compared with their wild-type counterparts. Clinical features, histologic score, and myeloperoxidase activity were significantly decreased in A(2B)AR(-/-) mice. However, A(2B)AR(-/-) showed increased susceptibility to systemic Salmonella infection. Tissue levels of the neutrophil chemokine, KC was decreased in colitic A(2B)AR(-/-) mice. In addition, flagellin-induced KC levels were attenuated in A(2B)AR(-/-) mice. Neutrophil chemotaxis in response to exogenous interleukin-8 was preserved in A(2B)AR(-/-) mice, suggesting intact neutrophil migration in response to appropriate stimuli.


CONCLUSIONS
These data demonstrate, for the first time, that the A(2B)AR plays a proinflammatory role in colitis. A(2B) receptor antagonism may be an effective treatment for acute inflammatory intestinal diseases such as acute flare of inflammatory bowel disease.
Kolachala
Vasantha L
VL
Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Vijay-Kumar
Matam
M
Dalmasso
Guillaiume
G
Yang
Dan
D
Linden
Joel
J
Wang
Lixin
L
Gewirtz
Andrew
A
Ravid
Katya
K
Merlin
Didier
D
Sitaraman
Shanthi V
SV
D000818:Animals; D054441:Cell Migration Assays, Leukocyte; D054360:Chemokine CXCL1 / Q000378:metabolism; D003092:Colitis / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004198:Disease Susceptibility; D005260:Female; D005408:Flagellin / Q000494:pharmacology; D017353:Gene Deletion; D018836:Inflammation Mediators / Q000378:metabolism; D016209:Interleukin-8 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000502:physiology*; D012480:Salmonella Infections / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D012486:Salmonella typhimurium; D014302:Trinitrobenzenesulfonic Acid
D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D018836:Inflammation Mediators; D016209:Interleukin-8; D043704:Receptor, Adenosine A2B; D005408:Flagellin; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D009195:Peroxidase