Adenosine receptors and modulation of natural killer cell activity by purine nucleosides

Natural killer (NK) cell activity is inhibited by the adenosine analogue tubercidin (Tub) and stimulated by the deoxyadenosine analogue 2-fluoro-1-beta-D-arabinofuranosyladenine 5'-monophosphate (F-ara-AMP) in the spleen lymphocytes from mice treated with the drugs in vivo (T. Priebe et al., Cancer Res., 48:4799, 1988). The present report demonstrates that the inhibition by Tub and stimulation by F-ara-AMP of NK cell activity are readily demonstrable in murine and human lymphocytes exposed to the drugs in vitro. In mouse spleen lymphocytes, NK cell activity is also inhibited by adenosine receptor A2 agonists, whereas potent A1 receptor agonists are more effective stimulators. Inhibition produced by adenosine, deoxyadenosine, and adenosine receptor agonists, but not by Tub, is partially prevented by the adenosine receptor antagonist 1,3-dipropyl-8-phenylxanthine amine congener. Agents that stimulate NK cell activity (deoxyadenosine, A1 receptor agonists, F-ara-AMP) do not increase further the 1.5-fold enhancement produced by a 10(-6) M concentration of 1,3-dipropyl-8-phenylxanthine amine congener. The nucleoside transport inhibitor, p-nitrobenzylthioinosine 5'-monophosphate, has no effect on NK cell activity or intracellular ribonucleotide pools; however, it partially prevents Tub 5'-triphosphate formation, ATP depletion, and NK cell inhibition in mouse spleen cells treated with Tub. p-Nitrobenzylthioinosine 5'-monophosphate also partially prevents the F-ara-AMP stimulation of NK cell activity, but it does not influence the effects of adenosine or deoxyadenosine. The results obtained with the adenosine receptor agonists suggest roles for both A1 and A2 receptors in regulating murine NK cell activity. Tub inhibition of NK cell activity does not appear to involve adenosine receptors; however, inhibition by the other agents may be mediated via an A2 receptor (stimulatory for adenylyl cyclase). Since p-nitrobenzylthioinosine 5'-monophosphate inhibited the stimulation of NK cell activity by F-ara-AMP, this stimulation may occur via an intracellular "P" site (inhibitory to adenylyl cyclase).