Hypertonic Stress Regulates T-Cell Function by the Opposing Actions of Extracellular Adenosine Triphosphate and Adenosine

Hypertonic saline (HS) treatment promotes interleukin (IL)-2 production and enhances T-cell activation by the release of cellular adenosine triphosphate (ATP) that activates P2 nucleotide receptors. Released ATP can be hydrolyzed to adenosine, which inhibits T-cell activation. We examined if adenosine affects the response of T cells to HS treatment, and found that the amount of ATP released from T cells is a function of the HS concentration and duration of HS exposure. Physiologically relevant HS concentrations (<40 mmol/L) induced rapid ATP release, with the highest ATP concentrations released within 1 min. The released ATP was converted to adenosine, which opposed the enhancing effects of HS on IL-2 production. We found that Jurkat and CD4+ primary human T cells express most abundantly the A2A and A2B adenosine receptor subtypes, which mediate the suppressive effects of adenosine, as the A2 receptor agonist CGS 21680 suppressed IL-2 production, whereas the A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl)xanthine augmented the enhancing effect of HS on T-cell function. Elimination of extracellular adenosine by adding exogenous adenosine deaminase also increased the enhancing effects of HS. These data suggest that the effect of HS treatment on T-cell function can be modulated with pharmacological agents that abolish the suppressive effects of adenosine formed from the ATP that is released in response to HS treatment. ABBREVIATIONS-(HS) hypertonic saline, (ADA) adenosine deaminase, (CPA) N6-cyclopentyladenosine, (CGS 21680) 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride, (IB-MECA) 1-deoxy-1-[6-[((3-iodophenyl)methyl)amino]-9H-purin-9-yl]-N-methyl-β-D-ribofuranuronamide N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide, (EHNA) erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride, (DIPY) dipyridamole, (SCH 58261) 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, (DMPX) 3,7-dimethyl-1-(2-propynyl)xanthine, (8-SPT) 8-(p-sulfophenyl) theophylline hydrate, (ΔΔCt) comparative threshold cycle