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

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 A(2A) receptor (A(2A)R) agonist (CGS21680) prevented leukocyte recruitment and reduced tumor necrosis factor alpha (TNF-alpha) 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 A(1) receptor (A(1)R) protein levels peak at 12 h after inoculation and then return to baseline at 24 h, whereas high affinity A(2A)R protein levels peak at 24 h concomitantly with the peak of adenosine concentration. Low affinity A(2B) receptor (A(2B)R) levels elevated slowly, remaining elevated up to 48 h. In human PMC (HPMC), the early cytokines, IL-1-alpha, and TNF-alpha upregulated the A(2B) and A(2A) receptors. However, interferon-gamma (IFN-gamma) upregulated the A(2B)R and decreased A(2A)R levels. Treatment with the A(2A)R 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 A(1)R dominates, and later its dominance is replaced by the G stimulatory (Gs) protein-coupled A(2A)R that suppresses inflammation. Early proinflammatory cytokines are an inducer of the A(2A)R 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.

Regulation of adenosine system at the onset of peritonitis

“…We have previously shown on PMCs and peritoneal leukocytes that A 1 R is up-regulated shortly after inoculation [13,14], and we now show that A 1 R is a potent promoter of inflammation in the peritoneum. Pre-treatment with DPCPX, an A 1 R antagonist, reduced both leukocyte recruitment and the pro-inflammatory cytokine production as expected; treatment with A 1 R agonist CCPA has the reverse effects on the inflammatory cytokines.…”

“…We have previously demonstrated in a peritonitis model that adenosine levels are up-regulated following E. coli inoculation [13]. In parallel to the induction of adenosine, A 1 R levels are up-regulated together with leukocyte recruitment at the initial phase of inflammation [13,14].…”

“…Engagement of A 2A R inhibits the activation of neutrophils, monocytes, platelets and T cells [9,11,12]. In a previous study using a mice peritonitis model, we demonstrated that, following inoculation with Escherichia coli, adenosine levels increased in the peritoneal cavity with a peak at 24h [13]. In addition, we found a sequential up-regulation of A 1 R and A 2A R on leukocytes and peritoneal mesothelial cells (PMCs).…”

“…Previously, we found that adenosine levels increase in the peritoneal cavity in response to E. coli inoculation [13]; therefore, we tested in vitro the regulation of adenosinemetabolizing enzymes in response to LPS. Treatment of PMCs with LPS up-regulated CD39 and CD73 levels.…”

Polimorfismos nos Receptores de Adenosina, suas Associações com Características Fisiopatológicas e Avaliação de Componentes na Biossíntese da Adenosina em Pacientes com Doença Falciforme.

“…ETHIER & MADISON, 2006;CLARK et al, 2007;BROWN et al, 2008).Estes são diferencialmente expressos no pulmão humano (VARANI et al, 2006). Sob condições fisiológicas normais, ARs A1 estão quiescentes, no entanto, são induzidos em condições de estresse, tais como isquemia, e em condições de inflamação, tipificado pelo envolvimento inflamatório das vias aéreas em humanos asmáticos (LAI et al, 2005;. ROGACHEV et al, 2006;.…”