Regulation of granulocyte apoptosis by NF-kappaB.
Granulocyte apoptosis is a crucial part of the successful resolution of inflammation. In vitro results show that activation of NF-kappaB (nuclear factor kappaB) in granulocytes is a survival mechanism. NF-kappaB inhibitors increase the rate of constitutive apoptosis in neutrophils and eosinophils and cause these cells to respond to the pro-apoptotic effects of TNF-alpha (tumour necrosis factor-alpha). Results from both in vivo and in vitro experiments suggest that there are at least two important waves of NF-kappaB activation in inflammatory loci, which increase the expression of COX-2 (cyclooxygenase-2), itself an NF-kappaB controlled gene. The first wave causes the production of inflammatory mediators such as PGE2 (prostaglandin E2), allowing the establishment of inflammation. The second wave causes the synthesis of PGD2 and its metabolites that induce granulocyte apoptosis by inhibiting NF-kappaB activation. These metabolites may therefore be important physiological mediators controlling the resolution of inflammation. Although NF-kappaB is an important target for anti-inflammatory therapy, the timing of inhibition in vivo may be crucial, to ensure that production of PGD2 and its sequential metabolites can occur.
Ward
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Respiratory Medicine Unit, MRC Centre for Inflammation Research, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG, UK. c.ward@ed.ac.uk
Walker
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A
Dransfield
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Haslett
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Rossi
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AG
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D051546:Cyclooxygenase 2; D003593:Cytoplasm / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006098:Granulocytes / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000628:therapy; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D015230:Prostaglandin D2 / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D014157:Transcription Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D015230:Prostaglandin D2