Cutting edge: purinergic signaling regulates radical-mediated bacterial killing mechanisms in macrophages through a P2X7-independent mechanism.
Signaling by extracellular nucleotides through P2 purinergic receptors affects diverse macrophage functions; however, its role in regulating antimicrobial radicals during bacterial infection has not been investigated. Mycobacterium tuberculosis-infected macrophages released ATP in a dose-dependent manner, which correlated with nitrite accumulation. P2 receptor inhibitors, including oxidized ATP, blocked NO synthase (NOSII) up-regulation and NO production induced by infection with M. tuberculosis or bacille Calmette-Guérin, or treatment with LPS or TNF-alpha. Oxidized ATP also inhibited oxygen radical production and activation of NF-kappaB and AP-1 in response to infection and inhibited NO-dependent killing of bacille Calmette-Guérin by macrophages. Experiments using macrophages derived from P2X7 gene-disrupted mice ruled out an essential role for P2X7 in NOSII regulation. These data demonstrate that P2 receptors regulate macrophage activation in response to bacteria and proinflammatory stimuli, and suggest that extracellular nucleotides released from infected macrophages may enhance production of oxygen radicals and NO at sites of infection.
Sikora
A
A
Department of Microbiology and Immunology, The Howard Hughes Medical Institute, Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Liu
J
J
Brosnan
C
C
Buell
G
G
Chessel
I
I
Bloom
B R
BR
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D005609:Free Radicals / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009163:Mycobacterium bovis / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction / Q000276:immunology*; D013498:Suramin / Q000494:pharmacology
D005609:Free Radicals; C546469:P2rx7 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D009569:Nitric Oxide; C017199:2',3'-dialdehyde ATP; D011732:Pyridoxal Phosphate; D013498:Suramin; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase