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Leukocyte populations change profoundly in the human endometrium during the menstrual cycle. However the predominant cell, the uterine natural killer (uNK) cell does not contain steroid receptors. From gene array analysis we identified a transcript encoding chemokine (C-X-C motif) ligand 14 (CXCL14) which is markedly up-regulated in the secretory phase of the cycle. We confirm this data by northern blotting and quantitative PCR. Using in situ hybridization we localized CXCL14 mRNA to the glandular epithelial cells where it was detected only in the secretory phase of the cycle. Candidate progesterone response elements were identified at positions -2028/- 2007 and -722/-697 (PRE1 and PRE2, respectively) relative to the translation start site. These were functionally tested using luciferase repor- ter deletion constructs, electrophoretic mobility shift assays and site-directed mutagenesis. The deletion/mutation of these sites reduced progesterone induction by 40 and 20%, respectively. Finally, we demonstrated that recombinant CXCL14 stimulated uNK cell chemotaxis in vitro. We therefore conclude that CXCL14 is likely to be regulated by progesterone in human endometrium and that it may exert a chemoattractive effect on uNK cells and in part be responsible for their clustering around the epithelial glands.

The endometrium is a dynamic tissue that undergoes periodic growth, remodeling and breakdown under the influence of ovarian steroid hormones. To investigate the molecular mechanisms underlying these processes, we used a murine model to mimic the decidualization and regression observed in humans. Ovariectomized mice were treated sequentially with steroid hormones, and subsequently, to induce decidualization, oil was injected into the uterine lumen. The animals were then divided into progesterone-maintained and progesterone-withdrawal groups. In the latter group, a process similar to menstruation was induced. The uterine tissues were collected at several time-points after the induction of decidualization. Histological analysis demonstrated that decidualization and tissue degeneration were successfully induced with similar features to those observed during the human menstrual cycle. Immunohistochemical, morphometric, and microarray-based techniques were used to study the cellular and molecular changes. The volume fractions of leukocytes, macrophages, and neutrophils, but not endothelial cells, increased in decidualized uteri and decreased after major tissue degradation was completed. The microarray data show that the levels of many transcripts that encode immune-related factors changed during the time-course used for this model, and the transcript levels of many of these factors paralleled the changes observed in the volume fractions of the immune cells. The results of the present study suggest that this model is a useful alternative to the use of non-human primates. Our findings also show that immune cells are recruited into the menstruating endometrium, and that immune-related genes are regulated in the uterus throughout menstruation.

The endometrium is a dynamic tissue that undergoes periodic growth, remodeling and breakdown under the influence of ovarian steroid hormones. To investigate the molecular mechanisms underlying these processes, we used a murine model to mimic the decidualization and regression observed in humans. Ovariectomized mice were treated sequentially with steroid hormones, and subsequently, to induce decidualization, oil was injected into the uterine lumen. The animals were then divided into progesterone-maintained and progesterone-withdrawal groups. In the latter group, a process similar to menstruation was induced. The uterine tissues were collected at several time-points after the induction of decidualization. Histological analysis demonstrated that decidualization and tissue degeneration were successfully induced with similar features to those observed during the human menstrual cycle. Immunohistochemical, morphometric, and microarray-based techniques were used to study the cellular and molecular changes. The volume fractions of leukocytes, macrophages, and neutrophils, but not endothelial cells, increased in decidualized uteri and decreased after major tissue degradation was completed. The microarray data show that the levels of many transcripts that encode immune-related factors changed during the time-course used for this model, and the transcript levels of many of these factors paralleled the changes observed in the volume fractions of the immune cells. The results of the present study suggest that this model is a useful alternative to the use of non-human primates. Our findings also show that immune cells are recruited into the menstruating endometrium, and that immune-related genes are regulated in the uterus throughout menstruation.