Purinergic receptors involved in the immunomodulatory effects of ATP in human blood

We recently showed that the physiological compound ATP simultaneously inhibited TNF-α and stimulated IL-10 release in LPS–PHA stimulated blood. The purpose of the present study was to determine the mechanism involved in the concerted modulatory effect of ATP on TNF-α and IL-10. Incubation of blood with ATP in the presence of selective P2 receptor antagonists showed that the stimulatory effect of ATP on IL-10 release was completely annihilated by both 2-MeSAMP (a P2Y12/13 receptor antagonist) and PSB-0413 (a P2Y12 receptor antagonist). On the other hand, the inhibitory effect of ATP on TNF-α release was completely reversed by 5′-AMPS (a P2Y11 receptor antagonist) as well as by H-89, an inhibitor of cAMP-activated PKA. The concerted inhibition by ATP of TNF-α release via P2Y11 activation and stimulation of IL-10 release via P2Y12 activation implicates a novel approach towards immunomodulation by altering the balance among pro- and anti-inflammatory cytokines.