Regulation of adenosine system at the onset of peritonitis

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BACKGROUND: Adenosine, a potent regulator of inflammation, is produced under stressful conditions due to degradation of ATP/ADP by the ectoenzymes CD39 and CD73. Adenosine is rapidly degraded by adenosine deaminase (ADA) or phosphorylated in the cell by adenosine kinase (AK). From four known receptors to adenosine, A(1) (A(1)R) promotes inflammation by a G(i)-coupled receptor. We have previously shown that A(1)R is up-regulated in the first hours following bacterial inoculation. The aim of the current study is to characterize the inflammatory mediators that regulate adenosine-metabolizing enzymes and A(1)R at the onset of peritonitis. METHODS: Peritonitis was induced in CD1 mice by intraperitoneal injection of Escherichia coli. TNFalpha and IL-6 levels were determined in peritoneal fluid by enzyme-linked immunosorbent assay. Adenosine-metabolizing enzymes and the A(1)R mRNA or protein levels were analyzed by quantitative PCR or by Western blot analysis, respectively. RESULTS: We found that CD39 and CD73 were up-regulated in response to bacterial stimuli (6-fold the basal levels), while AK and ADA mRNA levels were down-regulated. Cytokine production and leukocyte recruitment were enhanced (2.5-fold) by treatment with an A(1)R agonist (2-chloro-N(6)-cyclopentyladenosine, 0.1 mg/kg) and reduced (2.5-3-fold) by the A(1)R antagonist (8-cyclopentyl-1, 3-dipropylxanthine, 1 mg/kg). In contrast to lipopolysaccharide, IL-1, TNF and IFNgamma, only low IL-6 levels (0.01 ng/ml), in the presence of its soluble IL-6R (sIL-6R), were found to promote A(1)R expression on mesothelial cells. In mice, administration of neutralizing antibody to IL-6R or soluble gp130-Fc (sgp130-Fc) blocked peritoneal A(1)R up-regulation following inoculation. CONCLUSION: Bacterial products induce the production of adenosine by up-regulation of CD39 and CD73. Low IL-6-sIL-6R up-regulates the A(1)R to promote efficient inflammatory response against invading microorganisms.

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