Female steroid hormones regulate production of pro-inflammatory molecules in uterine leukocytes

Estrogens and progesterone could be among the environmental signals that govern uterine immune cell synthesis of pro-inflammatory substances. In order to investigate this possibility, we first mapped expression of the inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) genes in the leukocytes of cycling and pregnant mouse uteri, then tested the ability of estradiol-17 beta (E2) and progesterone to influence gene expression. Immunohistochemistry, in situ hybridization, and other experimental approaches, revealed that the iNOS and TNF-alpha genes are expressed in mouse uterine mast cells, macrophages and natural killer cells (uNK). Gene expression in each cell type was noted to be dependent upon stage of the cycle or stage of gestation, implying potential relationships with levels of female hormones and state of cell differentiation or activation. Further in vivo and in vitro experiments showed that individual hormones have cell type-specific effects on synthesis of iNOS and TNF-alpha that are exerted at the level of transcription. In uterine mast cells, iNOS and TNF-alpha are promoted by E2 whereas preliminary studies in macrophages suggest that transcription and translation of the two genes are unaffected by E2 but are inhibited by progesterone. Uterine NK cell production of iNOS and TNF-alpha is strongly related to cell differentiation, which is initiated and sustained by progesterone. Collectively, the results indicate that regulation of synthesis of pro-inflammatory molecules by hematopoietic cells in cycling and pregnant uterus comprises a new and potentially critical role for female steroid hormones.