Abstract
Interleukin 1beta (IL-1beta) suppresses the IL-6-dependent induction of type II acute-phase response genes, but the underlying mechanism for this suppression remains uncertain. Here we report that treatment of human hepatocullular carcinoma HepG2 cells with IL-1beta inhibited the IL-6-dependent binding of signal transducer and activator of transcription factor (STAT)1, but not that of STAT3, to the high-affinity serum-inducible element ('SIE'). Furthermore, IL-1beta selectively down-regulated the IL-6-induced tyrosine phosphorylation of STAT1 without affecting the level of STAT1 or tyrosine phosphorylation of STAT3. Kinase assays in vitro indicated that the inhibition of STAT1 phosphorylation by IL-1beta was not due to an upstream blockade of Janus kinase (JAK1 or JAK2) activation. However, pretreatment with the proteasome inhibitor MG132 under conditions that prevented the IL-1beta-dependent activation of the nuclear factor NF-kappaB also blocked the inhibitory effect of IL-1beta on IL-6-activated STAT1. In related experiments, the protein tyrosine phosphatase inhibitor Na(3)VO(4) also antagonized the inhibitory effect of IL-1beta on the activation of STAT1 by IL-6. Taken together, these findings indicate that, by using a proteasome-dependent mechanism, IL-1beta concomitantly induces NF-kappaB activation and dephosphorylates IL-6-activated STAT1; the latter might partly account for the inhibition by IL-1beta of the IL-6-dependent induction of type II acute-phase genes.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acute-Phase Proteins / genetics
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Cysteine Endopeptidases / metabolism*
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DNA / genetics
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DNA / metabolism
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / metabolism
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Down-Regulation / drug effects
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Enzyme Activation / drug effects
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Hepatocytes / drug effects
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Hepatocytes / enzymology
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Hepatocytes / metabolism
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Humans
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Interleukin-1 / pharmacology*
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Interleukin-6 / antagonists & inhibitors*
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Interleukin-6 / pharmacology
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Janus Kinase 1
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Janus Kinase 2
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Leupeptins / pharmacology
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Models, Biological
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Multienzyme Complexes / antagonists & inhibitors
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Multienzyme Complexes / metabolism*
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Mutation / genetics
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NF-kappa B / metabolism
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NF-kappaB-Inducing Kinase
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Phosphorylation / drug effects
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Phosphotyrosine / metabolism
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Proteasome Endopeptidase Complex
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Tyrosine Phosphatases / antagonists & inhibitors
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Protein Tyrosine Phosphatases / metabolism
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins*
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Receptor Cross-Talk*
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Signal Transduction / drug effects*
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / metabolism
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Tumor Cells, Cultured
Substances
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Acute-Phase Proteins
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DNA-Binding Proteins
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Interleukin-1
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Interleukin-6
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Leupeptins
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Multienzyme Complexes
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NF-kappa B
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Proto-Oncogene Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Trans-Activators
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Phosphotyrosine
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DNA
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Protein-Tyrosine Kinases
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JAK1 protein, human
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JAK2 protein, human
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Janus Kinase 1
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Janus Kinase 2
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Protein Serine-Threonine Kinases
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Protein Tyrosine Phosphatases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde