Cutting edge: Purinergic signaling regulates radical-mediated bacterial killing mechanisms in macrophages through a P2X(7)-independent mechanism

Signaling by extracellular nucleotides through P2 purinergic receptors affe cts diverse macrophage functions; however, its role in regulating antimicro bial radicals during bacterial infection has not been investigated, Mycobac terium tuberculosis-infected macrophages released ATP in a dose-dependent m anner. which correlated with nitrite accumulation. P2 receptor inhibitors, including oxidized ATP, blocked NO synthase (NOSII) up-regulation and NO pr oduction induced by infection with M. tuberculosis or bacille Calmette-Guer in, or treatment with LPS or TNF-alpha. Oxidized ATP also inhibited oxygen radical production and activation of NF-kappa B and AP-1 in response to inf ection and inhibited NO-dependent killing of bacille Calmette-Guerin by mac rophages, Experiments using macrophages derived from P2X(7) gene-disrupted mice ruled out an essential role for P2X(7) in NOSII regulation. These data demonstrate that P2 receptors regulate macrophage activation in response t o bacteria and proinflammatory stimuli, and suggest that extracellular nucl eotides released from infected macrophages may enhance production of oxygen radicals and NO at sites of infection.