Granulocyte-macrophage colony-stimulating factor (GM-CSF) targets myeloid leukocytes in the uterus during the post-mating inflammatory response in mice.

Factors in seminal plasma elicit a surge of GM-CSF expression in uterine epithelial cells after mating in mice. This study investigates the nature of the endometrial cell populations targeted by epithelial GM-CSF. In quantitative RT-PCR studies, expression of the alpha-subunit of the GM-CSF receptor (GM-CSF-R) parallelled GM-CSF expression, being maximal during the 48 h period after mating and declining thereafter. Expression of mRNA encoding beta-common chain (AIC2B) also increased after mating and remained high until the time of embryo implantation on day 4 of pregnancy. Cells expressing GM-CSF receptors were identified in sections of uterus on the day after mating using 125I-GM-CSF, and were located predominantly in the endometrial stroma subjacent to the luminal epithelium, co-localising with abundant populations of myeloid leukocytes. Cells expressing GM-CSF receptor were identified as macrophages, granulocytes and putative dendritic cells by flow cytometric analysis using lineage and receptor subunit specific antibodies. Recombinant GM-CSF injected into the uterine lumen of ovariectomised mice was found to elicit a dose-dependant accumulation of macrophages and granulocytes in the endometrium, in a pattern of distribution comparable to that seen in uteri after natural mating. Together, these data indicate a role for epithelial cell-derived GM-CSF in mediating the recruitment and potentially in modifying the behaviour of uterine leukocytes during the post-mating inflammatory response in mice.

The effect of restricted nutrition on uterine macrophage populations in mice.

The abundant macrophage populations present in the endometrium are implicated in the tissue remodelling events and immunological changes necessary for pregnancy. Using two regimens of restricted nutrition (95 and 88% of ad libitum intake for 19 days), we have shown that moderately reduced food consumption can dramatically alter the number of endometrial macrophages and their immunoaccessory function in mice. Restricted nutrition also interfered with the estrous cycle, but the effects on endometrial macrophages were more extensive and qualitatively different than could be explained by diminished ovarian steroid hormone activity. Significantly less F4/80+ and Ia+ cells were found in the endometrium of food restricted mice than in ad libitum mice at the same estrous cycle stage. In the more severely restricted mice the losses were even greater than those seen after ovariectomy. In ad libitum fed animals, uterine but not peritoneal macrophages showed an ovarian hormone-dependent inhibitory phenotype in a splenocyte mitogenesis assay. Macrophages derived from both locations exhibited greater immunostimulatory activity following restricted nutrition. We conclude that endometrial macrophage populations are influenced by nutritional status and this may be mediated through both steroid hormone-dependent and -independent mechanisms. Nutritionally induced aberrations in the number or behaviour of endometrial macrophages during the estrous cycle or in early pregnancy could have important implications for the quality of the pre- and peri-implantation environment and the maternal immune response to pregnancy.

Cytokine-leukocyte networks and the establishment of pregnancy.

PROBLEM: Factors in seminal plasma stimulate an intense but transient inflammatory response in the murine endometrium at mating. The aim of our current studies is to delineate the cytokine-leukocyte interactions comprising this response and to elucidate the significance of these events in changes in the maternal immune system and as determinants of pregnancy outcome. METHOD: We have reviewed our recent findings. RESULTS: Transforming growth factor (TGF)-beta1 has been identified as the inflammation-inducing moiety in seminal plasma. Seminal TGFbeta1 initiates endometrial leukocyte infiltration by up-regulating epithelial cell expression of granulocyte-macrophage colony-stimulating factor. Other cytokines and chemokines including regulated and normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and monocyte chemotactic protein-1 are also implicated as mediators of macrophage and granulocyte recruitment and activation. One consequence of this inflammatory response is the induction of a transient state of hyporesponsiveness to paternal major histocompatibility class I antigens. CONCLUSION: Our studies suggest that semen may play a critical role in providing the antigenic and environmental signals necessary to initiate an appropriate maternal immune response to the conceptus during pregnancy.