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 language | English |
|---|---|
| Pages (from-to) | 503-513 |
| Number of pages | 11 |
| Journal | Journal of Clinical Investigation |
| Volume | 104 |
| Issue number | 4 |
| Publication status | Published - Aug 1999 |
Fingerprint
ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD
AU - Srivastava, Sunil
AU - Weitzmann, M. Neale
AU - Cenci, Simone
AU - Ross, F. Patrick
AU - Adler, Stuart
AU - Pacifici, Roberto
PY - 1999/8
Y1 - 1999/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0032694582&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032694582&partnerID=8YFLogxK
M3 - Article
VL - 104
SP - 503
EP - 513
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 4
ER -