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The Roles of Inducible Nitric Oxide Synthase in Mediating the Effects of Embryotoxic Cytokines on Mouse Embryonic Cells

An early embryo is the most vulnerable stage in the life cycle of mammals, and it faces various immunologic challenges during the course of pregnancy. In particular, the blastocyst (the pre‐implantation embryo) is exposed to inflammatory cytokines resulting from the implantation process. Embryonic cells in the blastocyst have a dedicated task of rapid cell proliferation; how they deal with inflammatory cytokines known to negatively affect cell viability and proliferation is an important yet poorly understood question. We have investigated the effects of TNFα and IFNγ, two “embryotoxic cytokines” that impair blastocyst development and the process of implantation, on embryonic cells. Our results suggest that embryonic stem cells (ESCs), the pluripotent stem cells derived from the inner cell mass of the blastocyst, are insensitive to the cytotoxicity of TNFα and IFNγ. However, when ESCs are differentiated to fibroblasts (ESC‐FBs), they become susceptible to the cytotoxicity of TNFα and IFNγ. In particular, the combination of TNFα and IFNγ (TNFα/IFNγ) significantly reduced cell proliferation and induced apoptosis of ESC‐FBs. The cytotoxic effect of TNFα/IFNγ parallels the induction of nitric oxide synthase (iNOS) in ESC‐FBs, which has been known to cause cellular damage by producing nitric oxide (NO) as a free radical. In contrast, TNFα/IFNγ does not induce the expression of iNOS in ESCs or exert any detectable negative effects on cell proliferation and pluripotency of ESCs. However, ESCs are sensitive to the cytotoxicity of sodium nitroprusside, which can chemically generate NO in cell culture. Together, our results suggest that iNOS is a key effector molecule that mediates the cytotoxicity of TNFα/IFNγ in ESC‐FBs, but not in ESCs. Therefore, the lack of iNOS induction by TNFα/IFNγ in ESCs may be a protective mechanism that allows ESCs to avoid the cytotoxicity of the two cytokines. We are currently investigating the underlying molecular mechanisms and the biological implications of this finding.