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

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 A_2A receptor (A_2AR) 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 A_2AR protein levels peak at 24 h concomitantly with the peak of adenosine concentration. Low affinity A_2B receptor (A_2BR) levels elevated slowly, remaining elevated up to 48 h. In human PMC (HPMC), the early cytokines, IL-1-α, and TNF-α upregulated the A_2B and A_2A receptors. However, interferon-γ (IFN-γ) upregulated the A_2BR and decreased A_2AR levels. Treatment with the A_2AR 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 A_2AR that suppresses inflammation. Early proinflammatory cytokines are an inducer of the A_2AR 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.