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Tumor Necrosis Factor Regulation of Apoptosis in Mouse Preimplantation Embryos and Its Antagonism by Transforming Growth Factor Alpha/Phosphatidylionsitol 3-Kinase Signaling System¹

Departments of Obstetrics and Gynecology,³ and Dermatology and Plastic Surgery,⁴ Akita University School of Medicine, Akita, 010-8543 Japan

ABSTRACT

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.

apoptosis, embryo, gene regulation, growth factors, signal transduction

¹Supported by a Grant-in-Aid for Scientific Research (Grant-in-Aid for Young Scientists B: 177911010 [K.K.] and Grant-in-Aid for Scientific Research B: 18390444 [T.T.]) and the research funds from the Yamaguchi Endocrine Research Association (K.K.), the Kanae Foundation for Life and Socio-medical Science (K.K.), and the Kanzawa Medical Research Foundation (K.K.).

Correspondence: ²Kazuhiro Kawamura, Department of Obstetrics and Gynecology, Akita University School of Medicine, Hondo 1-1-1, Akita 010-8543, Japan. FAX: 81 18 884 6447; e-mail: kawamura{at}yf7.so-net.ne.jp

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