Qian Dong, Lin Hai-Yan, Wang Hong-Mei, Zhang Xuan, Liu Dong-Lin, Li Qing-Lei, Zhu Cheng
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, China.
Biol Reprod. 2004 Jun;70(6):1822-7. doi: 10.1095/biolreprod.103.025031. Epub 2004 Feb 11.
During early pregnancy, an environment of relative low oxygen tension is essential for normal embryonic and placental vasculature. In low-oxygen conditions, the hypoxic-inducible factor-1 (HIF-1), composed of alpha and beta subunits, controls the expression of a number of genes such as vascular endothelial growth factor (VEGF), a key angiogenic factor. The recent studies in some tumor cells have found that the labile component, HIF-1 alpha, is not only activated by hypoxia but also by peptides such as interleukin-1 (IL-1) in normoxia. In this article, we demonstrated that exposure of normal human cytotrophoblast cells to IL-1 beta stimulated the expression of HIF-1 alpha protein. Meanwhile, IL-1 beta also induced the secretion of VEGF in normal human cytotrophoblast cells. Our data indicated that IL-1 beta induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Moreover, treatment of cells with PD98059, an inhibitor of ERK1/2 signaling, inhibited the stimulation of HIF-1 alpha protein expression and VEGF secretion by IL-1 beta. These data indicate that, in normal human cytotrophoblast cells, IL-1 beta induces HIF- 1 alpha-mediated VEGF secretion and that IL-1 beta-stimulated ERK1/2 activation may be involved in this process.
在妊娠早期，相对低氧张力的环境对于正常胚胎和胎盘血管系统至关重要。在低氧条件下，由α和β亚基组成的缺氧诱导因子-1（HIF-1）控制许多基因的表达，如关键血管生成因子血管内皮生长因子（VEGF）。最近在一些肿瘤细胞中的研究发现，不稳定成分HIF-1α不仅在缺氧时被激活，在常氧下也可被白细胞介素-1（IL-1）等肽激活。在本文中，我们证明将正常人细胞滋养层细胞暴露于IL-1β可刺激HIF-1α蛋白的表达。同时，IL-1β也诱导正常人细胞滋养层细胞分泌VEGF。我们的数据表明，IL-1β诱导细胞外信号调节激酶（ERK）1/2磷酸化。此外，用ERK1/2信号抑制剂PD98059处理细胞可抑制IL-1β对HIF-1α蛋白表达和VEGF分泌的刺激。这些数据表明，在正常人细胞滋养层细胞中，IL-1β诱导HIF-1α介导的VEGF分泌，且IL-1β刺激的ERK1/2激活可能参与此过程。
