Abstract
Central to the bone-sparing effect of estrogen (E(2)) is its ability to block the monocytic production of the osteoclastogenic cytokine TNF-alpha (TNF). However, the mechanism by which E(2) downregulates TNF production is presently unknown. Transient transfection studies in HeLa cells, an E(2) receptor-negative line, suggest that E(2) inhibits TNF gene expression through an effect mediated by estrogen receptor beta (ERbeta). We also report that in RAW 264.7 cells, an E(2) receptor-positive murine monocytic line, E(2) downregulates cytokine-induced TNF gene expression by decreasing the activity of the Jun NH(2)-terminal kinase (JNK). The resulting diminished phosphorylation of c-Jun and JunD at their NH(2)-termini decreases the ability of these nuclear proteins to autostimulate the expression of the c-Jun and JunD genes, thus leading to lower production of c-Jun and JunD. The consequent decrease in the nuclear levels of c-Jun and JunD leads to diminished binding of c-Jun/c-Fos and JunD/c-Fos heterodimers to the AP-1 consensus sequence in the TNF promoter and, thus, to decreased transactivation of the TNF gene.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Base Sequence
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
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Cell Line
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DNA Primers / genetics
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Down-Regulation / drug effects
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Estradiol / pharmacology*
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Estrogen Receptor alpha
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Estrogen Receptor beta
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HeLa Cells
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Humans
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Interleukin-1 / pharmacology
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases*
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Monocytes / drug effects
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Monocytes / metabolism
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Phosphorylation
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Promoter Regions, Genetic
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Protein Binding
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Proto-Oncogene Proteins c-jun / biosynthesis*
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Proto-Oncogene Proteins c-jun / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Estrogen / drug effects
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Receptors, Estrogen / genetics
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Receptors, Estrogen / metabolism
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Transcription Factor AP-1 / metabolism
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics*
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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DNA Primers
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Estrogen Receptor alpha
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Estrogen Receptor beta
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Interleukin-1
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Proto-Oncogene Proteins c-jun
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RNA, Messenger
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Receptors, Estrogen
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Transcription Factor AP-1
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Tumor Necrosis Factor-alpha
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Estradiol
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases