Discrepancies were also reported among in vitro studies conducted by different teams, and distinct responses to IFN-т might depend upon the concentration or isoform used. Overall, this reminds us that care must be taken in evaluating observations made in vitro, and that performing in vivo protocols in parallel often offers physiological clarification. Although this may seem obvious, our own experience and examples from other labs prove this notion can often be forgotten. The sole expression of IFN receptors or any type of response to the molecule in vitro does not guarantee that stromal cells are a direct target of IFN-т or that the response obtained really has a physiological counterpart.
Three observations suggest that IFN-т acts primarily on cells of the LE and shallow glandular epithelium (sGE):
1) IFN receptors are mainly expressed in these cells, 2) binding of IFN-т is limited to these cells after intrauterine infusions, and 3) IFN-т is detectable only in these maternal cells during pregnancy. Thus, it is likely that the increase in several proteins (or encoding mRNAs) in the stroma or DG after in vivo treatments with IFN-т could be induced by intermediary molecules originating from the LE/sGE. Intraepithelial leukocytes are also a likely candidate because immune cells are very sensitive to IFN-т and respond to it with increased production of IFN-7, another IFN capable of duplicating some of the effects triggered by IFN-т.
This paper describes the first evidence that COX-2 and GM-CSF are up-regulated in vivo at the materno-fetal interface during the first month of gestation in the cow, particularly during the window of production of IFN-т by the conceptus. In accordance, COX-2 and GM-CSF were increased in the LE but not in the stroma of cows after intrauterine infusions of IFN-т. The results of the present study thus support the hypothesis that the embryo orchestrates the regulation of maternal mediators in favor of its survival and growth in two major ways during pregnancy recognition: 1) by modulating PG synthesis to protect both the corpus luteum from destruction and the conceptus from immune maternal rejection and 2) through GM-CSF, an an-tiapoptotic factor that promotes feto-placental development.