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(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.
Rogachev
B
B
Department of Nephrology, Soroka Medical Center and Ben-Gurion University of the Negev, Beer Sheva, Israel.
Ziv
N Y
NY
Mazar
J
J
Nakav
S
S
Chaimovitz
C
C
Zlotnik
M
M
Douvdevani
A
A
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D004926:Escherichia coli; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D010538:Peritonitis / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D010627:Phenethylamines / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism; D013805:Theobromine / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014970:Xanthines / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000959:Antihypertensive Agents; D015850:Interleukin-6; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C057837:3,7-dimethyl-1-propargylxanthine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D013805:Theobromine