Biphasic regulation of NF-kappa B activity underlies the pro- and anti-inflammatory actions of nitric oxide.
Expression of inducible NO synthase (iNOS) by macrophages is a prerequisite for the production of high output NO, which mediates many bactericidal and tumoricidal actions of these immune cells. The expression of iNOS in mammalian cells is governed predominantly by the transcription factor, NF-kappa B, which regulates the expression of many host defense proteins. In the present study, we characterize a novel, biphasic effect of NO on NF-kappa B activity in murine macrophages. This mechanism depends on the local concentration of NO and enables it both to up- and down-regulate the expression of host defense proteins including iNOS, cyclooxygenase-2, and IL-6. This biphasic activity of NO appears to play a pivotal role in the time course of activation of these immune cells and, by inference, in facilitating the initiation of a defense response against pathogenic stimuli and in its termination to limit tissue damage. This mechanism may explain at least in part the reported ability of NO to act in both a pro- and anti-inflammatory manner.
Connelly
L
L
Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
Palacios-Callender
M
M
Ameixa
C
C
Moncada
S
S
Hobbs
A J
AJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001120:Arginine / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003470:Culture Media; D051546:Cyclooxygenase 2; D004338:Drug Combinations; D004357:Drug Synergism; D006834:Hydrazines / Q000494:pharmacology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009589:Nitrogen Oxides; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013997:Time Factors; D000093242:Interleukin-6 Inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001120:Arginine; D003470:Culture Media; D051546:Cyclooxygenase 2; D004338:Drug Combinations; D006834:Hydrazines; D018836:Inflammation Mediators; D015850:Interleukin-6; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D009589:Nitrogen Oxides; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; D000093242:Interleukin-6 Inhibitors; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; C496317:Nos2 protein, mouse