Primary human uterine, cervical, and ectocervical stromal fibroblasts constitutively secrete hepatocyte growth factor (HGF), yet only uterine stromal fibroblasts increase HGF secretion in response to estradiol. Estradiol-induced HGF secretion by uterine stromal fibroblasts may have a significant effect on uterine cancer and endometriosis.
"In previous studies we have seen differential responses between fibroblasts from different sites in the FRT. For example, whereas E2 stimulates hepatocyte growth factor (HGF) secretion by EM fibroblasts, it had no effect on CX and ECX fibroblast secretion of HGF . In response to E2, EM epithelial cell secretion of HBD2 and Elafin increased, but was inhibited when vaginal epithelial cells were treated with E2
[Show abstract][Hide abstract] ABSTRACT: The conflicting results of recent pre-exposure prophylaxis (PrEP) trials utilizing tenofovir (TFV) to prevent HIV infection in women led us to evaluate the accumulation of intracellular TFV-diphosphate (TFV-DP) in cells from the female reproductive tract (FRT) and whether sex hormones influence the presence of TFV-DP in these cells. Following incubation with TFV, isolated epithelial cells, fibroblasts, CD4+ T cells and CD14+ cells from the FRT as well as blood CD4+ T cells and monocyte-derived macrophages convert TFV to TFV-DP. Unexpectedly, we found that TFV-DP concentrations (fmol/million cells) vary significantly with the cell type analyzed and the site within the FRT. Epithelial cells had 5-fold higher TFV-DP concentrations than fibroblasts; endometrial epithelial cells had higher TFV-DP concentrations than cells from the ectocervix. Epithelial cells had 125-fold higher TFV-DP concentrations than FRT CD4+ T cells, which were comparable to that measured in peripheral blood CD4+ T cells. These findings suggest the existence of a TFV-DP gradient in the FRT where epithelial cells > fibroblasts > CD4+ T cells and macrophages. In other studies, estradiol increased TFV-DP concentrations in endometrial and endocervical/ectocervical epithelial cells, but had no effect on fibroblasts or CD4+ T cells from FRT tissues. In contrast, progesterone alone and in combination with estradiol decreased TFV-DP concentrations in FRT CD4+ T cells. Our results suggest that epithelial cells and fibroblasts are a repository of TFV-DP that is under hormonal control. These cells might act either as a sink to decrease TFV availability to CD4+ T cells and macrophages in the FRT, or upon conversion of TFV-DP to TFV increase TFV availability to HIV-target cells. In summary, these results indicate that intracellular TFV-DP varies with cell type and location in the FRT and demonstrate that estradiol and/or progesterone regulate the intracellular concentrations of TFV-DP in FRT epithelial cells and CD4+ T cells.
PLoS ONE 06/2014; 9(6):e100863. DOI:10.1371/journal.pone.0100863 · 3.23 Impact Factor
"For instance, progesterone depletion leads to the up-regulation of IL-8, MCP-1, and COX-2, resulting in the activation of monocytes and neutrophils and finally, up-regulation of matrix metalloproteinases for initiation of menstruation. As an indirect effect, estradiol treatment leads to up-regulation of hepatocyte growth factor (HGF) secretion that in turn regulates TNFα and MIP3α/CCL20 production by uterine epithelial cells. Thus, concentrations of chemokines and cytokines will vary in the endometrium during normal physiological processes, as well as pathological conditions, such as infection and endometriosis. "
[Show abstract][Hide abstract] ABSTRACT: The mucosal immune system in the female reproductive tract (FRT) is well equipped to meet the sexually transmitted pathogens, allogeneic sperm, and the immunologically distinct fetus. Analysis of the FRT indicates that epithelial cells provide a physical barrier against pathogens and microbial infections as well as secretions containing anti-microbial peptides, cytokines, and chemokines which recruit and activate immune cells. Epithelial and immune cells confer protection in part through Toll-like receptors. The aim of this literature is to review the diverse components of the innate immune system, contributing to an exclusive protection system throughout the FRT.
"Previously, we found that FRT epithelial cells and fibroblasts were capable of both mounting an immune response and modulating immune cell function –. In addition, the secretion of immune factors by these FRT cells is under hormonal control –. Acting directly via hormone receptors and indirectly through cytokines, chemokines, and growth factors, estradiol and progesterone selectively enhance and suppress elements of the immune system during the menstrual cycle to optimize conditions for reproductive success . By inhibiting immune responses to sperm and a non-syngeneic fetus during the secretory phase of the menstrual cycle, the chances for conceptus/fetus survival is increased. "
[Show abstract][Hide abstract] ABSTRACT: The use of topical and oral adenosine derivatives in HIV prevention that need to be maintained in tissues and cells at effective levels to prevent transmission prompted us to ask whether estradiol could influence the regulation of catabolic nucleotidase enzymes in epithelial cells and fibroblasts from the upper and lower female reproductive tract (FRT) as these might affect cellular TFV-DP levels. Epithelial cells and fibroblasts were isolated from endometrium (EM), endocervix (CX) and ectocervix (ECX) tissues from hysterectomy patients, grown to confluence and treated with or without estradiol prior to RNA isolation. The expression of nucleotidase (NT) genes was measurable by RT-PCR in epithelial cells and fibroblasts from all FRT tissues. To determine if sex hormones have the potential to regulate NT, we evaluated NT gene expression and NT biological activity in FRT cells following hormone treatment. Estradiol increased expression of Cytosolic 5'-nucleotidase after 2 or 4 h in endometrial epithelial cells but not epithelial cells or fibroblasts from other sites. In studies using a modified 5'-Nucleotidase biological assay for nucleotidases, estradiol increased NT activity in epithelial cells and fibroblasts from the EM, CX and ECX at 24 and 48 h. In related studies, HUVEC primary cells and a HUVEC cell line were unresponsive to estradiol in terms of nucleotidase expression or biological activity. Our findings of an increase in nucleotidase expression and biological activity induced by estradiol do not directly assess changes in microbicide metabolism. However, they do suggest that when estradiol levels are elevated during the menstrual cycle, FRT epithelial cells and fibroblasts from the EM, CX and ECX have the potential to influence microbicide levels that could enhance protection of HIV-target cells (CD4+T cells, macrophages and dendritic cells) throughout the FRT.
PLoS ONE 07/2013; 8(7):e69854. DOI:10.1371/journal.pone.0069854 · 3.23 Impact Factor
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