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C entral 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.J. Clin. Invest. 104:503-513 (1999).