Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD

Sunil Srivastava, M. Neale Weitzmann, Simone Cenci, F. Patrick Ross, Stuart Adler, Roberto Pacifici

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Abstract

Central to the bone-sparing effect of estrogen (E2) is its ability to block the monocytic production of the osteoclastogenic cytokine TNF-α (TNF). However, the mechanism by which E2 downregulates TNF production is presently unknown. Transient transfection studies in HeLa cells, an E2 receptor- negative line, suggest that E2 inhibits TNF gene expression through an effect mediated by estrogen receptor β (ERβ). We also report that in RAW 264.7 cells, an E2 receptor-positive murine monocytic line, E2 downregulates cytokine-induced TNF gene expression by decreasing the activity of the Jun NH2-terminal kinase (JNK). The resulting diminished phosphorylation of c-Jun and JunD at their NH2-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.

Original languageEnglish
Pages (from-to)503-513
Number of pages11
JournalJournal of Clinical Investigation
Volume104
Issue number4
Publication statusPublished - Aug 1999

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JNK Mitogen-Activated Protein Kinases
Estrogens
Down-Regulation
jun Genes
Cytokines
Gene Expression
Transcription Factor AP-1
Consensus Sequence
Nuclear Proteins
HeLa Cells
Estrogen Receptors
Transcriptional Activation
Transfection
Phosphorylation
Bone and Bones
Genes
RAW 264.7 Cells

ASJC Scopus subject areas

  • Medicine(all)

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Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD. / Srivastava, Sunil; Weitzmann, M. Neale; Cenci, Simone; Ross, F. Patrick; Adler, Stuart; Pacifici, Roberto.

In: Journal of Clinical Investigation, Vol. 104, No. 4, 08.1999, p. 503-513.

Research output: Contribution to journalArticle

Srivastava, S, Weitzmann, MN, Cenci, S, Ross, FP, Adler, S & Pacifici, R 1999, 'Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD', Journal of Clinical Investigation, vol. 104, no. 4, pp. 503-513.
Srivastava, Sunil ; Weitzmann, M. Neale ; Cenci, Simone ; Ross, F. Patrick ; Adler, Stuart ; Pacifici, Roberto. / Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD. In: Journal of Clinical Investigation. 1999 ; Vol. 104, No. 4. pp. 503-513.
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