A2A adenosine receptor (AR) activation inhibits pro-inflammatory cytokine production by human CD4+ helper T cells and regulates Helicobacter-induced gastritis and bacterial persistence.
Helicobacter pylori causes a lifelong infection and provides a model of bacterial adaptation and persistent colonization. Adenosine is an anti-inflammatory mediator that limits tissue damage during inflammation. We studied the role of adenosine in the T-cell-mediated regulation of gastritis and bacterial persistence. After 4 h of activation, human T helper (Th) cells increased A(2A) adenosine receptor (A(2A)AR) mRNA level (sevenfold). A(2A)AR was the predominant subtype expressed in resting and stimulated gastric or peripheral Th cells. Stimulation with ATL313, an A(2A)AR agonist, increased cyclic AMP (cAMP) accumulation and reduced interleukin-2 (IL-2) production by 20-50%. ATL313 also attenuated tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) production, which was inhibited by an A(2A)AR antagonist. Infection of IL-10-deficient mice with H. pylori is cleared spontaneously due to the marked inflammation. Administration of ATL313 during infection reduced gastritis and pro-inflammatory cytokine responses while bacterial load increased. In contrast, infection of A(2A)AR-deficient mice enhanced gastritis. Thus, A(2A)AR limits the pro-inflammatory effects of Th cells and favor chronic Helicobacter infection.
Alam
M S
MS
Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Kurtz
C C
CC
Wilson
J M
JM
Burnette
B R
BR
Wiznerowicz
E B
EB
Ross
W G
WG
Rieger
J M
JM
Figler
R A
RA
Linden
J
J
Crowe
S E
SE
Ernst
P B
PB
D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D005753:Gastric Mucosa / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D005756:Gastritis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D016481:Helicobacter Infections / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D044922:Helicobacter felis; D016480:Helicobacter pylori; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C510376:ATL 313; D058908:Adenosine A2 Receptor Agonists; D015704:CD4 Antigens; D016207:Cytokines; D007376:Interleukin-2; D010880:Piperidines; D043705:Receptor, Adenosine A2A; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D000242:Cyclic AMP