Role of embryonic factors in human implantation.

Implantation biology is now at a stage where experimental science will be very productive in answering basic questions about the ability of an embryo to implant. The advancement of our knowledge of cytokines and growth factors has been critically important in fuelling the recent new understanding of embryo implantation. Specifically, our increased knowledge of the interleukin (IL)-1 system, as well as leukaemia-inhibiting factor (LIF), epidermal growth factor and colony-stimulating factor-1, and the availability of recombinant protein, specific antibodies and knockout mice, have led to a more detailed outline of implantation events. LIF and IL-1 are the two systems where recent advances have suggested their importance in implantation events. Recently, LIF has been shown in mice to be an endometrial requirement for implantation and embryo development. Although LIF is a pleiotropic molecule, with many interactions in multiple body tissues, in the uterus, concentrations are elevated on day 4 of pregnancy. Experiments with knockout mice have shown the requirement for endometrial LIF for successful implantation. The IL-1 system, consisting of two agonists (IL-1 alpha and IL-1 beta), two receptors (IL-1R types I and II) and the homologous IL-1 receptor antagonist (ra), has also been studied. Knowledge that the embryo secretes IL-1 suggested the interaction between embryonic IL-1 and endometrial receptor, which has been shown to occur. IL-1R type I is plentiful on endometrial epithelial cells and appears to interact with embryonically secreted IL-1 beta to favour implantation. Such implantation events in vivo in mice are blocked by the introduction of large quantities of IL-1ra, consistent with the hypothesis that appropriate interactions between agonist and receptor at the level of the endometrial surface are a requisite for successful implantation. As more specific information on each cytokine or growth factor system comes to light, more complete information on the multiple molecular steps of implantation will become apparent. However, it is clear that no single cytokine or growth factor will be able to explain the complicated events of embryo implantation. Such an important necessary phenomenon has multiple redundancies. The interactions between cytokines and growth factors are becoming increasingly apparent and will need more experimental evidence before a full understanding of implantation is available.