Sun W H, Keller E T, Stebler B S, Ershler W B
Department of Pediatrics, Children's Memorial Hospital, Chicago, Illinois, USA.
Biochem Biophys Res Commun. 1998 Mar 27;244(3):691-5. doi: 10.1006/bbrc.1998.8324.
Estrogen (E2) is known to prevent bone loss and the mechanism is, at least in part, mediated by inhibition of expression of cytokines such as interleukin-6 (IL-6). Expression of IL-6 is tightly regulated and the transcription factor NF kappa B can upregulate IL-6 gene expression by binding to its promoter region. NF kappa B is kept in an inactive state by associating with its cytoplasmic inhibitor I kappa B alpha. Upon mitogenic stimulation, I kappa B alpha becomes phosphorylated, followed by a rapid protein degradation. As a result, NF kappa B is released and translocate to the nucleus where DNA binding occurs. It has been shown that E2 treatment downregulates mitogen-induced IL-6 expression by inhibiting NF kappa B activity. Here, we sought to determine whether E2 regulates IL-6 gene expression by modulating the levels of I kappa B alpha. Our results show that E2 treatment almost completely inhibits phorbol ester-induced I kappa B alpha protein degradation. In addition, E2 inhibits phorbol ester-stimulated I kappa B alpha gene expression. Taken together, our results suggest that E2 maintains steady state levels of I kappa B alpha upon mitogen stimulation, resulting in inhibition of NF kappa B activation and IL-6 gene expression. This may explain the protective effect of E2 on bone loss.
已知雌激素（E2）可预防骨质流失，其机制至少部分是通过抑制细胞因子如白细胞介素-6（IL-6）的表达来介导的。IL-6的表达受到严格调控，转录因子核因子κB（NFκB）可通过结合其启动子区域上调IL-6基因表达。NFκB通过与其细胞质抑制剂IκBα结合而保持无活性状态。在有丝分裂原刺激后，IκBα被磷酸化，随后迅速发生蛋白质降解。结果，NFκB被释放并转运至细胞核，在细胞核中发生DNA结合。研究表明，E2处理通过抑制NFκB活性下调有丝分裂原诱导的IL-6表达。在此，我们试图确定E2是否通过调节IκBα的水平来调控IL-6基因表达。我们的结果表明，E2处理几乎完全抑制佛波酯诱导的IκBα蛋白质降解。此外，E2抑制佛波酯刺激的IκBα基因表达。综上所述，我们的结果表明，E2在有丝分裂原刺激后维持IκBα的稳态水平，从而抑制NFκB活化和IL-6基因表达。这可能解释了E2对骨质流失的保护作用。
