Adenosine is upregulated during peritonitis and is involved in downregulation of inflammation

B. Rogachev, N. Y. Ziv, J. Mazar, S. Nakav, C. Chaimovitz, M. Zlotnik, A. Douvdevani

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Loss of function of the peritoneal membrane is associated with peritonitis. Adenosine levels in sites of inflammation were shown to increase and exhibit immunoregulatory effects. Our aim was to elucidate the regulatory role of adenosine during peritonitis and to test the involvement of peritoneal mesothelial cells (PMC) in adenosine regulation. In a mice model of Escherichia coli peritonitis, the adenosine A2A receptor (A2AR) agonist (CGS21680) prevented leukocyte recruitment and reduced tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels. Peritonitis induced the elevation of adenosine with a peak at 24 h. Analysis of adenosine receptor levels on peritoneum showed that A1 receptor (A1R) protein levels peak at 12 h after inoculation and then return to baseline at 24 h, whereas high affinity A2AR protein levels peak at 24 h concomitantly with the peak of adenosine concentration. Low affinity A2B receptor (A2BR) levels elevated slowly, remaining elevated up to 48 h. In human PMC (HPMC), the early cytokines, IL-1-α, and TNF-α upregulated the A2B and A2A receptors. However, interferon-γ (IFN-γ) upregulated the A2BR and decreased A2AR levels. Treatment with the A2AR agonist reduced IL-1-dependent IL-6 secretion from HPMC. In conclusion, the kinetics of adenosine receptors suggest that at early stage of peritonitis, the A1R dominates, and later its dominance is replaced by the G stimulatory (Gs) protein-coupled A2AR that suppresses inflammation. Early proinflammatory cytokines are an inducer of the A2AR and this receptor reduces their production and leukocyte recruitment. Future treatment with adenosine agonists should be considered for attenuating the damage to mesothelium during the course of acute peritonitis.

Original languageEnglish
Pages (from-to)675-681
Number of pages7
JournalKidney International
Volume70
Issue number4
DOIs
StatePublished - 28 Aug 2006

Keywords

  • Adenosine
  • Inflammation
  • Peritoneal membrane
  • Peritonitis

ASJC Scopus subject areas

  • Nephrology

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