Abstract
Progression of inflammatory processes correlates with the release of cell-derived mediators from the local site of inflammation. These mediators, including cytokines of the IL-1 and IL-6 families, act on host cells and exert their action by activating their signal transduction pathways leading to specific target gene activation. Parthenolide, a sesquiterpene lactone found in many medical plants, is an inhibitor of IL-1-type cytokine signaling that blocks the activation of NF-kappaB. Here we show that parthenolide is also an effective inhibitor of IL-6-type cytokines. It inhibits IL-6-type cytokine-induced gene expression by blocking STAT3 phosphorylation on Tyr705. This prevents STAT3 dimerization necessary for its nuclear translocation and consequently STAT3-dependent gene expression. This is a new molecular mechanism of parthenolide action that additionally explains its anti-inflammatory activities.
Copyright 2000 Academic Press.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute-Phase Proteins / metabolism
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Carcinoma, Hepatocellular
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Cytokines / pharmacology*
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Interleukin-1 / pharmacology
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Interleukin-6 / pharmacology*
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Liver Neoplasms
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism*
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Oncostatin M
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Peptides / pharmacology
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Recombinant Fusion Proteins / biosynthesis
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STAT3 Transcription Factor
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Sesquiterpenes / pharmacology*
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Signal Transduction / drug effects*
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Signal Transduction / physiology
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Trans-Activators / metabolism*
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Transcriptional Activation
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Transfection
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Tumor Cells, Cultured
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alpha 1-Antichymotrypsin / genetics
Substances
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Acute-Phase Proteins
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Cytokines
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DNA-Binding Proteins
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Interleukin-1
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Interleukin-6
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NF-kappa B
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OSM protein, human
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Peptides
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Recombinant Fusion Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Sesquiterpenes
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Trans-Activators
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alpha 1-Antichymotrypsin
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Oncostatin M
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parthenolide