Possible new role for NF-kappaB in the resolution of inflammation.
Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Although much attention has focused on pro-inflammatory pathways that initiate inflammation, relatively little is known about the mechanisms that switch off inflammation and resolve the inflammatory response. The transcription factor NF-kappaB is thought to have a central role in the induction of pro-inflammatory gene expression and has attracted interest as a new target for the treatment of inflammatory disease. We show here that NF-kappaB activation in leukocytes recruited during the onset of inflammation is associated with pro-inflammatory gene expression, whereas such activation during the resolution of inflammation is associated with the expression of anti-inflammatory genes and the induction of apoptosis. Inhibition of NF-kappaB during the resolution of inflammation protracts the inflammatory response and prevents apoptosis. This suggests that NF-kappaB has an anti-inflammatory role in vivo involving the regulation of inflammatory resolution.
Lawrence
T
T
Department of Experimental Pathology, William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, UK. t.lawrence@mds.qmw.ac.uk
Gilroy
D W
DW
Colville-Nash
P R
PR
Willoughby
D A
DA
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D017209:Apoptosis; D002351:Carrageenan / Q000009:adverse effects; D003546:Cysteine Endopeptidases; D005260:Female; D006099:Granuloma / Q000139:chemically induced / Q000276:immunology*; D007249:Inflammation; D007962:Leukocytes / Q000276:immunology*; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles; D010998:Pleurisy / Q000139:chemically induced / Q000276:immunology*; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D013450:Sulfones; D013859:Thiocarbamates / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein
D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; C416282:BAY 11-7085; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011759:Pyrrolidines; D013450:Sulfones; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D013859:Thiocarbamates; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C020972:pyrrolidine dithiocarbamic acid; D002351:Carrageenan; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde