Embryonic resistance to tumour necrosis factor-α mediated cytotoxicity: novel mechanism underlying maternal immunological tolerance to the fetal allograft

Abstract

The cytokine tumour necrosis factor-α (TNFα) has been postulated to play an essential role in the cytotoxic activity of cell-mediated immunity against allogenic or tumour cells invading the host. Several tumour cell lines, however, are resistant to TNF mediated cytotoxicity and respond paradoxically by cellular proliferation and by autocrine secretion of TNFα. In view of the metastatic character of the mammalian embryo, the aim of this study was to assess the potential of murine embryos to secrete TNFα in vitro, to express TNF receptors and to resist TNFα mediated cytotoxicity during their in-vitro development to the blastocyst stage. The potential of human embryos to secrete TNFα in vitro until the blastocyst stage was also investigated. From a total of 11 human embryos, which were allowed to proceed to blastocyst formation, seven secreted TNFα in the range of 2–117 pg/ml/24 h. A total of 123 C57BL/6J mouse embryos were studied of which 55% secreted TNFα in the range of 1.25–3.95 mg/ml/24 h. The presence of high levels of exogenous TNFα (10–300 IU) was not detrimental to the in-vitro development of murine embryos. Using immunohistochemical techniques, we were not able to detect the presence of type I or II TNF receptors on the surface of murine embryos. Our findings suggest that human and C57BL/6J murine embryos have the potential to secrete TNFα in vitro during the developmental stages leading to blastocyst formation. In both species, the presence of TNFα in the culture medium did not cause subsequent necrosis of the conceptus, suggesting that mammalian embryos may be TNFα resistant cell lines. The observed embryonic resistance to TNFα may be explained by the absence of TNF receptors by which the cytotoxic effect is usually mediated. It is suggested that embryonic resistance to physiological concentrations of TNFα released by effectors of the host's immune system, could be via a mechanism underlying the maternal immunological tolerance to the fetal allograft.