NDT Advance Access published online on October 26, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp542
Regulation of adenosine system at the onset of peritonitis
1 Department of Clinical Biochemistry, Soroka Medical University Center and Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel 2 Department of Nephrology, Soroka Medical University Center and Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel 3 Department of General Surgery, Soroka Medical University Center and Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel
Correspondence and offprint requests to: Correspondence and offprint requests to: Amos Douvdevani; E-mail: amosd{at}bgu.ac.il
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Abstract |
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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, A1 (A1R) promotes inflammation by a Gi-coupled receptor. We have previously shown that A1R 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 A1R at the onset of peritonitis.
Methods. Peritonitis was induced in CD1 mice by intraperitoneal injection of Escherichia coli. TNF
and IL-6 levels were determined in peritoneal fluid by enzyme-linked immunosorbent assay. Adenosine-metabolizing enzymes and the A1R 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 A1R agonist (2-chloro-N6-cyclopentyladenosine, 0.1 mg/kg) and reduced (2.5–3-fold) by the A1R antagonist (8-cyclopentyl-1, 3-dipropylxanthine, 1 mg/kg). In contrast to lipopolysaccharide, IL-1, TNF and IFN
, only low IL-6 levels (0.01 ng/ml), in the presence of its soluble IL-6R (sIL-6R), were found to promote A1R expression on mesothelial cells. In mice, administration of neutralizing antibody to IL-6R or soluble gp130-Fc (sgp130-Fc) blocked peritoneal A1R 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 A1R to promote efficient inflammatory response against invading microorganisms.
Keywords: A1 Adenosine receptor; C39; CD73; peritonitis; soluble-interleukin (IL)-6 receptor
Received for publication: 6. 4.09
Accepted in revised form: 20. 9.09