Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD
Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD
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DOI：
10.1172/jci7094
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发表时间：
1999-08-01
影响因子：
15.9
通讯作者：
Pacifici, R
中科院分区：
文献类型：
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作者：
Srivastava, S;Weitzmann, MN;Pacifici, R
雌激素 (E-2) 的骨保护作用的核心是它能够阻止破骨细胞因子 TNF-α (TNF) 的单核细胞产生。然而，E-2 下调 TNF 产生的机制目前尚不清楚。 HeLa 细胞（一种 E-2 受体阴性细胞系）的瞬时转染研究表明，E-2 通过雌激素受体 β (ER β) 介导的作用抑制 TNF 基因表达。我们还报道，在 RAW 264.7 细胞（一种 E-2 受体阳性鼠单核细胞系）中，E-2 通过降低 Jun NH2 末端激酶 (JNK) 的活性来下调细胞因子诱导的 TNF 基因表达。由此产生的 c-Jun 和 JunD 在其 NH2 末端磷酸化的减少降低了这些核蛋白自动刺激 c-Jun 和 JunD 基因表达的能力，从而导致 c-Jun 和 JunD 的产量降低。随后 c-Jun 和 JunD 核水平的降低导致 c-Jun/c-Fos 和 JunD/c-Fos 异二聚体与 TNF 启动子中 AP-1 共有序列的结合减少，从而减少 TNF 基因的反式激活。
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.