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

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 (ER beta). 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 NH2-terminal kinase (JNK). The resulting diminished phosphorylation of c-Jun and JunD at their NH2-terminal 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.