atl-313 and Helicobacter-Infections

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.

Topics: Adenosine A2 Receptor Agonists; Animals; CD4 Antigens; Cyclic AMP; Cytokines; Gastric Mucosa; Gastritis; Helicobacter felis; Helicobacter Infections; Helicobacter pylori; Humans; Interferon-gamma; Interleukin-10; Interleukin-2; Lymphocyte Activation; Mice; Mice, Knockout; Piperidines; Receptor, Adenosine A2A; T-Lymphocytes, Helper-Inducer; Tumor Necrosis Factor-alpha