Molecular regulation of uterine leukocyte recruitment during early pregnancy in the mouse

Abstract

Summary The pre-implantation period in the mouse is characterized by a dramatic but transient inflammation-like reaction induced in the endometrium by seminal vesicle-derived moieties in the ejaculate including TGFβ. Leukocytes infiltrating the endometrium during this response are implicated in the immunological changes and extensive tissue remodeling required to accommodate the conceptus during implantation and placental development. The movements and functional behavior of these cells are thought to be orchestrated by a precisely regulated, sequential release of cytokines from the uterine epithelium. GM-CSF and CSF-1 are two epithelial cytokines implicated in the recruitment and phenotypic regulation of the abundant populations of endometrial macrophages, granulocytes and dendritic cells. Studies in genetically cytokine-deficient mice have been undertaken to determine the physiological significance of GM-CSF and CSF-1. The inflammatory response was found to occur despite the absence of one or both of these cytokines, albeit with moderate differences in the numbers, phenotype and activation state of the recruited cells. Expression of mRNAs for other potential regulators of uterine leukocytes was investigated using semi-quantitative RT-PCR. Messenger RNA encoding chemokines of the C-C family (RANTES, MCP-1, MIP-1α, MIP-1β and eotaxin) and C-X-C family (MIP-2 and KC) were all transiently induced during the 24–28 hour period after mating. Ovarian steroid hormones and possibly factors in semen are implicated in the regulation of chemokine mRNA expression. These studies indicate that an array of chemokines are likely to have principal roles in the extravasation and migration of inflammatory leukocytes into the uterine stromal tissue, with GM-CSF, CSF-1 and other epithelial cytokines acting to regulate the subsequent differentiation and activation phenotype of recruited cells.