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Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD
Sunil Srivastava, … , Stuart Adler, Roberto Pacifici
Sunil Srivastava, … , Stuart Adler, Roberto Pacifici
Published August 15, 1999
Citation Information: J Clin Invest. 1999;104(4):503-513. https://doi.org/10.1172/JCI7094.
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Article

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

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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.

Authors

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

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In vitro E2 treatment of RAW 264.7 cells decreases IL-1– and TNF-induced...
In vitro E2 treatment of RAW 264.7 cells decreases IL-1– and TNF-induced production of TNF. (a) Levels (mean ± SEM of 4 experiments) of TNF in the culture medium as assayed by an ELISA specific for murine TNF. Equal numbers of cells were stimulated with murine IL-1 and human TNF (5 ng/mL of each) and then treated with either control vehicle or E2 (10–8 M) for 24 hours. *P < 0.05 vs. untreated cells. (b) TNF mRNA expression, as assessed by Northern blot analysis. Cells were treated with either control vehicle or E2 (10–8 M) for 24 hours and stimulated with IL-1 and TNF (5 ng/mL of each) during the last 4 hours of incubation. Representative data from 1 of 3 replicate experiments.

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