title: A2B adenosine receptor gene deletion attenuates murine colitis.
abstract: 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.
authors.affiliation: Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Vasantha L
authors.initials: VL
authors.lastname: Kolachala
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
authors.forename: Guillaiume
authors.initials: G
authors.lastname: Dalmasso
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
authors.forename: Lixin
authors.initials: L
authors.lastname: Wang
authors.forename: Andrew
authors.initials: A
authors.lastname: Gewirtz
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
authors.forename: Shanthi V
authors.initials: SV
authors.lastname: Sitaraman
mesh_terms: 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
chemical_list: 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