Tumor necrosis factor regulation of apoptosis in mouse preimplantation embryos and its antagonism by transforming growth factor alpha/phosphatidylionsitol 3-kinase signaling system
Tumor necrosis factor regulation of apoptosis in mouse preimplantation embryos and its antagonism by transforming growth factor alpha/phosphatidylionsitol 3-kinase signaling system
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DOI：
10.1095/biolreprod.106.058008
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发表时间：
2007-04-01
影响因子：
3.6
通讯作者：
Tanaka, Toshinobu
中科院分区：
文献类型：
--
作者：
Kawamura, Kazuhiro;Kawamura, Nanami;Tanaka, Toshinobu
着床前胚胎细胞的存活和凋亡是成功妊娠的基础。与这些过程相关的是，哺乳动物的输卵管和子宫产生肿瘤坏死因子（TNF）和转化生长因子α (TGFA)。在早期胚胎中，TNF诱导细胞凋亡，而TGFA可作为存活因子。本研究探讨了TNF对小鼠早期胚胎细胞凋亡的调控作用及其与TGFA的拮抗作用。TNF受体超家族成员1a mRNA在胚胎早期均可检测到，在囊胚早期后增加，而TNF受体超家族成员1b转录本仅在囊胚扩大期检测到。虽然妊娠子宫产生TNF，但植入前的生理水平较低。TNF抑制了两细胞期胚胎向囊胚的发育，在体外和体内均表现出增殖减少和凋亡增加。TNF对早期胚胎发育和存活的这些有害影响被一种中和性抗TNF抗体阻断。除了死亡受体介导的途径外，tnf诱导的凋亡还通过线粒体功能的破坏进一步介导，其特征是细胞色素c的释放和caspase 9的激活。TNF与TGFA共处理可抵消其对囊胚的促凋亡作用。TGFA对tnf诱导的细胞凋亡的拮抗作用被磷脂酰狮醇3-激酶（PI3K）抑制剂阻断。本研究结果表明，小鼠着床前胚胎对TNF诱导凋亡具有分期选择性易感性，TGFA/PI3K信号系统在控制TNF诱导的囊胚凋亡中具有重要作用。
Survival and apoptosis of cells in preimplantation embryos are fundamental for successful pregnancy. Relevant to these processes, tumor necrosis factor (TNF) and transforming growth factor alpha (TGFA) are produced by mammalian oviducts and uteri. In early embryos, TNF induces apoptosis, whereas TGFA could act as a survival factor. Here we investigated the TNF regulation of apoptosis in early mouse embryos and its antagonism by TGFA. TNF receptor superfamily, member 1a mRNA was detectable throughout early embryonic stages, with an increase after the early blastocyst stage, whereas the expression of TNF receptor superfamily, member 1b transcripts were detected only at the expanded blastocyst stage. Although pregnant uteri produced TNF, physiologic levels were low during the preimplantation period. Treatment with TNF inhibited the development of two-cell stage embryos to blastocysts showing decreased proliferation and increased apoptosis both in vitro and in vivo. These detrimental effects of TNF on early embryo development and survival were blocked by a neutralizing anti-TNF antibody. In addition to the death receptor-mediated pathway, TNF-induced apoptosis was further mediated by disruption of mitochondrial functions, characterized by release of cytochrome c and activation of caspase 9. The proapoptotic effects of TNF in blastocysts were counteracted by cotreatment with TGFA. The antagonistic effect of TGFA on TNF-induced apoptosis was blocked by phosphatidylionsitol 3-kinase (PI3K) inhibitors. The present findings demonstrate the stage-selective susceptibility to the apoptosis-inducing effect of TNF in mouse preimplantation embryos and that the TGFA/PI3K signaling system has an important role in the control of TNF-induced apoptosis in blastocysts.