Abstract
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.
MeSH terms
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Animals
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Anti-Infective Agents / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / metabolism*
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Apoptosis*
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Carrageenan / adverse effects
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Cysteine Endopeptidases
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Female
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Granuloma / chemically induced
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Granuloma / immunology*
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Inflammation
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Leukocytes / immunology*
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Leupeptins / pharmacology
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Male
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Mice
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Multienzyme Complexes / antagonists & inhibitors
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism*
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Nitriles
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Pleurisy / chemically induced
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Pleurisy / immunology*
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Proteasome Endopeptidase Complex
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Protein Binding / drug effects
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins c-bcl-2*
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Pyrrolidines / pharmacology
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Rats
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Sulfones
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Thiocarbamates / pharmacology
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta1
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Tumor Suppressor Protein p53 / biosynthesis
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bcl-2-Associated X Protein
Substances
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Anti-Infective Agents
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Anti-Inflammatory Agents, Non-Steroidal
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BAY 11-7085
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Leupeptins
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Multienzyme Complexes
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NF-kappa B
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Nitriles
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyrrolidines
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Sulfones
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Tgfb1 protein, mouse
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Tgfb1 protein, rat
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Thiocarbamates
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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pyrrolidine dithiocarbamic acid
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Carrageenan
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde