Biomedical subjects

G Mor

Publications and source records attributed to G Mor.

At least 19 recordsLinked to original sources

PubMed2007

Trophoblast-macrophage interactions: a regulatory network for the protection of pregnancy.

PROBLEM: Macrophages are one of the first immune cells observed at the implantation site. Their presence has been explained as the result of an immune response toward paternal antigens. The mechanisms regulating monocyte migration and differentiation at the implantation site are largely unknown. In the present study, we demonstrate that trophoblast cells regulate monocyte migration and differentiation. We propose that trophoblast cells 'educate' monocytes/macrophages to create an adequate environment that promote trophoblast survival. METHOD OF STUDY: CD14(+) monocytes were isolated from peripheral blood using magnetic beads. Co-culture experiments were conducted using a two-chamber system. Monocytes were stimulated with lipopolysaccharide (LPS) and cytokine levels were determined using multiplex cytokine detecting assay. RESULTS: Trophoblast cells increase monocyte migration and induce a significant increase in the secretion and production of the pro-inflammatory cytokines [interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha] and chemokines (growth-related oncogen-alpha, monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta, RANTES). Furthermore, the response of monocytes to LPS was different in monocytes pre-exposed to trophoblast cells. CONCLUSION: The results of this study suggest that trophoblast cells are able to recruit and successfully educate monocytes to produce and secrete a pro-inflammatory cytokine and chemokine profile supporting its growth and survival. Furthermore we demonstrate that trophoblast cells can modulate monocytes response to bacterial stimuli.

Cell Communication↗

PubMed2006

Dermatitis as a component of the fetal inflammatory response syndrome is associated with activation of Toll-like receptors in epidermal keratinocytes.

AIMS: Microbial invasion of the amniotic cavity (MIAC) elicits a fetal inflammatory response such as funisitis and chorionic vasculitis. However, little is known about the changes of fetal skin during MIAC. Toll-like receptors recognize microbial products and initiate an immune response. The aims of this study were to examine histopathological features of fetal skin exposed to MIAC and to assess the changes in Toll-like receptor (TLR)-2 and TLR-4 expression. METHODS AND RESULTS: Skin samples were obtained from fetal autopsies (n = 12). The cases were classified according to the presence (n = 8) or absence (n = 4) of acute chorioamnionitis and analysed by immunohistochemistry using a panel of antibodies. Leucocytic infiltrates into the superficial dermis were observed in cases with chorioamnionitis; the majority of inflammatory cells were neutrophils, lymphocytes and histiocytes. TLR-2 immunoreactivity in the skin was stronger in fetuses with chorioamnionitis than in those without this condition. However, immunoreactivity of TLR-4 in the fetal skin was constitutively expressed, regardless of the presence or absence of chorioamnionitis. CONCLUSIONS: This study demonstrates for the first time that fetal dermatitis can be detected and is part of the fetal inflammatory response syndrome (FIRS). We propose that this 'FIRS-associated fetal dermatitis' is a fetal counterpart of chorioamnionitis.

Abnormalities, Multiple↗

PubMed2005

Down-regulation of Bcl-2 enhances estrogen apoptotic action in long-term estradiol-depleted ER(+) breast cancer cells.

Postmenopausal women with estrogen receptor positive (ER(+)) breast cancer frequently respond paradoxically to estrogen administration with tumor regression. Using both LTED and E8CASS cells derived from MCF-7 breast cancer cells by long-term estrogen-deprivation, we previously reported that 17beta -estradiol (estradiol) is a powerful, pro-apoptotic hormone which kills the cancer cells through activation of the Fas/FasL death receptor pathway. We postulated that the mitochondrial interactive protein Bcl-2 might play a role in the regulation of estradiol-induced apoptosis in both LTED and E8CASS cells. In this study, we assessed estradiol effects on cell growth, proliferation and apoptosis. Additionally we investigated the effect of estradiol on caspase activation, NF-KB and Bcl-2 expression. The functional role of Bcl-2 in estradiol-induced apoptosis was further studied by knockdown or decrease of Bcl-2 with siRNA. Our results show that estradiol significantly inhibited cell growth primarily through a pro-apoptotic action involving caspase-7 and 9 activations (p < 0.01). Basal Bcl-2 and NF-KB levels were greatly elevated and estradiol decreased NF-KB, but not Bcl-2 expression. Knockdown of Bcl-2 expression with siRNA decreased the levels of this protein by 9 fold (p < 0.01). This reduction markedly sensitized both LTED and E8CASS cells to the pro-apoptotic action of estradiol, leading to a synergistic induction of apoptosis and a concomitant reduction in cell number (p < 0.01). Therefore, down-regulation of Bcl-2 synergistically enhanced estradiol-induced apoptosis in ER(+) postmenopausal breast cancer cells.

Apoptosis↗

PubMed2005

Toll-like receptors and their role in the trophoblast.

The aim of this review is to discuss the role of Toll-like receptors at the maternal-fetal interface and the capacity of trophoblast cells to initiate innate immune responses towards infection. The maternal-fetal interface represents an immunologically unique site that must promote tolerance to the allogenic fetus, whilst maintaining host defense against a diverse array of possible pathogens. Clinical studies have shown a strong association between certain complications of pregnancy and intrauterine infections. Therefore, innate immune responses against microorganisms at the maternal-fetal interface may have a significant impact on the success of a pregnancy. There is growing evidence that trophoblast cells are able to recognize and respond to pathogens through the expression of Toll-like receptors, an important part of innate immunity. This review will discuss the role of Toll-like receptors at the maternal-fetal interface, the potential for trophoblast cells to function as components of the innate immune system and the impact TLR-mediated trophoblast responses may have on pregnancy outcome.

Adult↗

PubMed2005

Metalloproteinase expression by control and telomerase immortalized human endometrial endothelial cells.

Vascular endothelial cells play a critical role in the maintenance of endometrial homeostasis. Indeed many pathological conditions causing abnormal endometrial bleeding including progestin only contraception, hormone replacement therapy, endometrial polyps, myomas, hyperplasia and cancer are associated with aberrant angiogenesis. Critical to the process of angiogenesis is the breakdown of the surrounding tissues by matrix metalloproteases (MMPs). In addition to the cells surrounding the endometrial endothelial cells, the endothelial cells themselves produce their own panel of MMPs. We now characterize the specific MMPs that are expressed by endothelial cells derived from human endometrium. These include MMP-1, MMP-2 and MMP-10 but not MMP-3. In addition, in order to successfully carry out consistent, homogeneous and sufficient numbers of studies we investigated the in vitro expression of the MMPs with both freshly isolated, early passaged endometrial endothelial cells (HEECs) as well as with newly telomerase immortalized HEECs (T-HEECs). The latter were karyotypically normal and expressed classic endothelial cell endpoints such as tubulogenesis on matrigel and expression of the endothelial cell markers CD-31 (PECAM), von Willebrand's factor, and the Tie-2 receptors. The levels of MMP expression as well as that of the metalloprotease inhibitors TIMP-1 and TIMP-2 were similar in parent and immortalized endothelial cells.

Cell Line, Transformed↗

PubMed2003

Uncoupling proteins-2 and 3 influence obesity and inflammation in transgenic mice.

OBJECTIVE: To test the hypothesis that either uncoupling protein-2 UCP2 or UCP3 or both together influence obesity and inflammation in transgenic mice. DESIGN: We generated 12 lines of transgenic mice for both human UCP2 and 3 using native promoters from a human bacterial artificial chromosome (BAC) clone. The BAC expresses no genes other than UCP2 and 3. Mice used for experiments are N4 or higher of backcross to C57BL/6J (B6). Each experiment used transgenic mice and their nontransgenic littermates. RESULTS: Northern blots confirmed expression on human UCP2 in adipose and spleen, while human UCP3 expression was detectable in gastrocnemius muscle. Western blots demonstrated a four-fold increase of UCP2 protein in spleens of Line 32 transgenic animals. Heterozygous mice of four lines showing expression of human UCP2 in spleen were examined for obesity phenotypes. There were no significant differences between Lines 1 and 32, but female transgenics of both lines had significantly smaller femoral fat depots than the control (littermate) mice (P=0.015 and 0.005, respectively). In addition, total fat of transgenic females was significantly less in Line 1 (P=0.05) and almost significantly different in Line 32 (P=0.06). Male Line 1 mice were leaner (P=0.04) while male Line 32 mice were almost significantly leaner (P=0.06). Heterozygous mice of Lines 35 and 44 showed no significant differences from the nontransgenic littermate controls. Effects of the UCP2/UCP3 transgene on obesity in Line 32 mice were confirmed by crossing transgenic mice with the B6.Cg-Ay agouti obese mice. B6.Cg-Ay carrying the UCP2/UCP3 transgene from Line 32 were significantly leaner than nontransgenic B6.Cg-Ay mice. Line 32 UCP2/UCP3 transgenics showed increased hypothalamic Neuropeptide (NPY) levels and food intake, with reduced spontaneous physical activity. Transgenic baseline interleukin4 (IL-4) and interleukin6 (IL-6) levels were low with lower or later increases after endotoxin injection compared to wild-type littermates. Endotoxin-induced fever was also diminished in transgenic male animals. Low-density lipoprotein (LDL) cholesterol levels were significantly higher in both Line 1 and 32 transgenics (P=0.05 and 0.001, respectively) after they had been placed on a moderate fat-defined diet containing 32% of calories from fat for 5 weeks. CONCLUSION: Moderate overexpression of UCP2 and 3 reduced fat mass and increased LDL cholesterol in two independent lines of transgenic mice. Thus, the reduced fat mass cannot be due to insertional mutagenesis since virtually identical fat pad weights and masses were observed with the two independent lines. Line 32 mice also have altered inflammation and mitochondrial function. We conclude that UCP2 and/or 3 have small but significant effects on obesity in mice, and that their mechanism of action may include alterations of metabolic rate.

Adipose Tissue↗

PubMed2003

Maternal serum of women with pre-eclampsia reduces trophoblast cell viability: evidence for an increased sensitivity to Fas-mediated apoptosis.

OBJECTIVE: Pre-eclampsia or 'toxemia of pregnancy' has been attributed to the presence of a circulating 'toxin' which disappears from peripheral blood after delivery of the placenta. However, the presence, nature and effects of this toxin have eluded characterization. Increased trophoblast apoptosis has been observed in the placenta of women with pre-eclampsia, and it is possible that this biological phenomenon is important for the genesis of the disease and mediated through a soluble factor(s) present in maternal blood. This study was designed to test the hypothesis that serum from women with pre-eclampsia changes trophoblast viability. Moreover, we sought to examine whether this effect could be mediated through changes in sensitivity to Fas/Fas ligand-mediated apoptosis. STUDY DESIGN: H8 trophoblast cells were cultured with serum obtained from normal pregnant women (n = 48) and patients with pre-eclampsia (n = 12). Cell viability was determined by the Cell Titer 96 assay. Fas sensitivity was determined by treating the cells with an agonist anti-Fas antibody or a blocking anti-Fas ligand antibody. RESULTS: Serum from normal pregnant women did not affect trophoblast cell viability. In contrast, serum from pre-eclamptic women reduced trophoblast viability, and this was enhanced by treatment with an anti-Fas antibody. This effect was reversed by the treatment with a blocking anti-Fas ligand antibody. CONCLUSION: Serum from women with pre-eclampsia induces the cytotoxicity of a first-trimester trophoblast cell line (H8). This effect appears to be related to changes in trophoblast sensitivity to Fas-mediated apoptosis. These findings suggest that a factor present in the maternal blood of patients with pre-eclampsia may have a role in the genesis of the syndrome.

Apoptosis↗

PubMed2001

Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol.

BACKGROUND: High doses of estrogen can promote tumor regression in postmenopausal women with hormone-dependent breast cancer, but the mechanism is unknown. We investigated the molecular basis of this process by using LTED cells, which were derived by growing MCF-7 breast cancer cells under long-term (6-24 months) estrogen-deprived conditions. METHODS: We treated LTED and MCF-7 cells with various concentrations of 17beta-estradiol (estradiol) and assayed their growth by counting the cells and measured apoptosis by annexin V staining and DNA fragmentation. Using western blot analysis, we also examined the expression of the apoptosis-inducing system of the Fas death receptor protein and its ligand, FasL, in these cells. To assess the involvement of Fas and FasL in the induction of apoptosis in LTED cells, we used activating anti-Fas antibodies and the universal caspase inhibitor Z-VAD. Finally, we examined the expression of Fas protein in E8CASS and BSK3 cells, two other cell lines derived by depriving MCF-7 cells of estrogen long term, and the responses of these cells to high-dose estradiol. All statistical tests were two-sided. RESULTS: High concentrations of estradiol (>or=0.1 nM) resulted in a statistically significant, 60% reduction in the growth of LTED cells (P< .001) and in a sevenfold increase in apoptosis (P< .001) as compared with levels in vehicle-treated cells. Both LTED and MCF-7 cells expressed FasL, but only LTED cells expressed Fas. Treatment of LTED cells with 0.1 nM estradiol increased the expression of FasL. Activating anti-Fas antibodies increased apoptosis of LTED cells, which was further stimulated by estradiol. Z-VAD blocked estradiol-induced apoptosis. E8CASS cells, which express Fas protein, but not BSK3 cells, which do not, also responded to 0.1 nM estradiol by increasing apoptosis. CONCLUSION: Tumor regression induced by high-dose estrogen therapy in postmenopausal woman may result from estrogen activation of Fas-mediated apoptosis.

Apoptosis↗

PubMed2001

Estrogen and the aging brain.

Evidence is presented indicating a role for estrogen in the function and maintenance of the aging brain. Based on complementary data that estrogen regulates the function of the immune--brain barrier, the hypothesis is presented that estrogen contributes to brain homeostasis via regulation of microglial activation, enabling immune-privileged status in the brain. Diminished estrogen levels during the menopause compromise the immune--brain barrier fostering inflammatory processes in the brain. This has potentially lethal consequences for brain cells, and may contribute to brain pathologies such as Alzheimer's disease.

Aged↗

PubMed2001

Serum soluble Fas levels in preeclampsia.

OBJECTIVE: To determine if serum soluble Fas levels are altered in women with preeclampsia. METHODS: Thirty-four pregnant women with preeclampsia and 34 normotensive pregnant women were studied. Subjects were matched as much as possible for demographics. Preeclampsia was defined as proteinuric hypertension. Serum soluble Fas levels were measured by enzyme-linked immunoassay. Two-tailed Student t test, chi(2) test, Pearson correlation coefficients, and analysis of variance with post hoc test were used for statistical analyses. RESULTS: Mean serum soluble Fas levels were significantly higher in preeclamptic than normotensive women (10.59 +/- 0.68 U/mL versus 5.65 +/- 0.35 U/mL, P <.001). CONCLUSION: Elevated serum soluble Fas is associated with preeclampsia. Such elevation might indicate protection of maternal T-lymphocyte apoptosis and consequently lead to the maternal immune intolerance noted in preeclampsia.

Adult↗

PubMed2001

17alpha-methyl testosterone is a competitive inhibitor of aromatase activity in Jar choriocarcinoma cells and macrophage-like THP-1 cells in culture.

17alpha-methyl testosterone is a synthetic androgen with affinity for the androgen receptor. 17alpha-methyl testosterone is used widely as a component of hormone replacement therapy. Previous reports have indicated that contrary to testosterone, 17alpha-methyl testosterone is not aromatized. However, 17alpha-methyl testosterone still could affect local estrogen formation by regulating aromatase expression or by inhibiting aromatase action. Both possibilities have important clinical implications. To evaluate the effect of 17alpha-methyl testosterone on the expression and activity of aromatase, we tested the choriocarcinoma Jar cell line, a cell line that express high levels of P450 aromatase, and the macrophage-like THP-1 cells, which express aromatase only after undergoing differentiation. We found that in both cell lines, 17alpha-methyl testosterone inhibits aromatase activity in a dose-related manner. The curve of inhibition parallels that of letrozole and gives complete inhibition at 10(-4) M 17alpha-methyl testosterone, determined by the tritium release assay. 17alpha-methyl testosterone does not have detectable effects on aromatase RNA and protein expression by Jar cells. Undifferentiated THP-1 cells had no aromatase activity and showed no effect of 17alpha-methyl testosterone, but differentiated THP-1 (macrophage-like) cells had a similar inhibition of aromatase activity by 17alpha-methyl testosterone to that seen in Jar cells. The Lineweaver-Burke plot shows 17alpha-methyl testosterone to be a competitive aromatase inhibitor. Our results show for the first time that 17alpha-methyl testosterone acts as an aromatase inhibitor. These findings are relevant for understanding the effects of 17alpha-methyl testosterone as a component of hormone replacement therapy. 17alpha-methyl testosterone may, as a functional androgen and orally active steroidal inhibitor of endogenous estrogen production, also offer special possibilities for the prevention/treatment of hormone-sensitive cancers.

Aromatase↗

PubMed2001

The role of the Fas/Fas ligand system in estrogen-induced thymic alteration.

PROBLEM: Estrogen induces atrophy in the thymus by an unknown mechanism. Since the Fas/FasL system is one of the main pathways in T cell apoptosis, we tested the hypothesis that estrogen-induced thymic atrophy is mediated by the Fas/FasL system. METHODS OF STUDY: In vivo experiments were done using ovariectomized female rats treated with estrogen or saline. In vitro experiments were performed using isolated thymocytes. Estrogen receptor (ER) alpha and beta expression was characterized using flow cytometry, RT-PCR and immunofluorescence. Fas and FasL mRNA and protein expression was evaluated using RT-PCR and Western blot analysis respectively. RESULTS: ERalpha and ERbeta are present in thymocytes and stromal cells. ER expression is mainly localized in the Double Positive CD4+CD8+ thymocytes. Estrogen treatment decreases thymus size and increase FasL expression. CONCLUSION: CD4+CD8+ thymocytes and thymic stroma cells express ERalpha and ERbeta. In vivo and in vitro we showed that estrogen treatment increases FasL expression while decreasing thymus cell number. These findings support the hypothesis that estrogen-induced thymic atrophy occurs as a result of apoptosis and is mediated by estrogen-induced FasL expression.

Animals↗

PubMed2001

Plasmid DNA vaccines. Immunology, tolerance, and autoimmunity.

DNA vaccination is a novel approach for inducing an immune response. Purified plasmid DNA containing an antigen's coding sequences and the necessary regulatory elements to express them is introduced into the tissue via intramuscular injection or particle bombardment. Once the DNA reaches the tissue, the antigen is expressed in enough quantity to induce a potent and specific immune response and to confer protection against further infections. The effectiveness of DNA vaccines against viruses, parasites, and cancer cells has been demonstrated in numerous animal models. This new approach comes as an aid for the prevention of infectious diseases for which the conventional vaccines have failed. DNA vaccine research is providing new insights into some of the basic immunological mechanisms of vaccination such as antigen presentation, the role of effector cells, and immunoregulatory factors. In addition, DNA vaccines may enable us to manipulate the immune system in situations where the response to agents is inappropriate or ineffective. The study of the potential deleterious effects of DNA vaccines is furthering our knowledge regarding the relationship between bacterial DNA and the immune system, as well as its potential application for the study of neonatal tolerance and autoimmunity.

Animals↗

PubMed2000

Estrogen-regulated developmental neuronal apoptosis is determined by estrogen receptor subtype and the Fas/Fas ligand system.

Adult sexual dimorphism in neuronal cell number is controlled by estrogen exposure during a tightly defined period of rat brain development. The mechanisms of estrogen's effect are unknown; one possibility is regulation of programmed cell death (apoptosis). In this study we have shown that estradiol can function as a neuroprotective agent or an inducer of apoptosis, depending on the estrogen receptor-subtype present in the cell. Thus, ERalpha has a neuroprotective effect, while ERbeta mediates the induction of apoptosis in neuronal cells. Moreover, we show that estrogen-induced apoptosis through ER-beta requires the expression of Fas- and Fas ligand (FasL) proteins, since the absence of FasL in neurons prevents this effect. Furthermore, we demonstrate that microglia-secreted products induce the expression of FasL necessary to mediate estradiol-ERbeta apoptotic effect. These findings may explain the dichotomous effect of fetal estradiol on the adult neuronal number.

Animals↗

PubMed2000

Reactive astrocytes upregulate Fas (CD95) and Fas ligand (CD95L) expression but do not undergo programmed cell death during the course of anterograde degeneration.

Tissue homeostasis is determined by a balance between proliferation and apoptosis. Various lesions in the brain are accompanied by proliferation and subsequent death of glial cells, but the mechanisms that limit this expansion of glial populations remains unknown. One possible candidate is the death ligand, FasL, and its receptor Fas, because the expression of both proteins was reported on glial cells. To elucidate the expression and putative function of Fas and FasL on proliferative glial cells, we performed stereotactic lesion of the entorhinal cortex of adult rats. Such lesions induce proliferation of astrocytes and microglial cells in the hippocampal fields of anterograde degeneration. Subsequently, the total number of both cell types returns to pre-lesion counts. We found that Fas and FasL is strongly upregulated on astrocytes in the zone of anterograde degeneration with a peak 5 days postlesion (dpl) and a return to control levels at 10 dpl. However, evidence for astrocytic cell death was neither detected by TUNEL staining, immunocytochemistry for c-Jun, and apoptosis-specific protein (ASP), nor by staining for morphologic hallmarks of apoptotic or necrotic cell death at the light and electron microscopic level. Thus, increased expression of Fas and FasL is not accompanied by cell death of reactive astrocytes during anterograde degeneration.

Animals↗

PubMed2000

Absence of estrogen receptor-beta expression in metastatic ovarian cancer.

OBJECTIVE: To evaluate the expression of estrogen receptor (ER)alpha and ERbeta mRNA and protein in normal ovarian tissue and primary and metastatic tumors. METHODS: Estrogen receptor alpha and ERbeta expression was studied in normal ovarian biopsies (n = 9) and primary (n = 8) and metastatic ovarian epithelial cancers (n = 8). Ovarian tissue was collected from surgical samples. Estrogen receptor alpha and ERbeta mRNA expression was compared by coamplification of the mRNA of the ERs. Expression was confirmed at the protein level by Western blot analysis using antibodies specific for each receptor. RESULTS: Among eight primary ovarian cancer samples, three had only ERalpha, two had only ERbeta, and three had both. All eight metastatic ovarian cancer tissues expressed only ERalpha mRNA and protein. Biopsies from normal ovaries had ERalpha and ERbeta mRNA and protein. Two of the ovarian epithelial cancer samples were paired and showed the same results. CONCLUSION: We found varying amounts of ERalpha and ERbeta in normal ovaries, lower levels of ERbeta expression in ovarian epithelial cancer primary tumors, and only ERalpha in metastatic tumors. Our findings indicate that a fundamental difference might exist between primary and metastatic cells, which could be caused by intrinsic or extrinsic factors that regulate ER gene expression.

Adenocarcinoma, Mucinous↗

PubMed2000

Tissue-specific synthesis and oxidative metabolism of estrogens.

Estrogen exposure represents the major known risk factor for development of breast cancer in women and is implicated in the development of prostate cancer in men. Human breast tissue has been shown to be a site of oxidative metabolism of estrogen due to the presence of specific cytochrome P450 enzymes. The oxidative metabolism of 17beta-estradiol (E2) to E2-3,4-quinone metabolites by an E2-4-hydroxylase in breast tissue provides a rational hypothesis to explain the mammary carcinogenic effects of estrogen in women because this metabolite is directly genotoxic and can undergo redox cycling to form genotoxic reactive oxygen species. In this chapter, evidence in support of this hypothesis and of the role of P4501B1 as the 4-hydroxylase expressed in human breast tissue is reviewed. However, the plausibility of this hypothesis has been questioned on the grounds that insufficient E2 is present in breast tissue to be converted to biologically significant amounts of metabolite. This critique is based on the assumption that plasma and tissue E2 levels are concordant. However, breast cancer tissue E2 levels are 10-fold to 50-fold higher in postmenopausal women than predicted from plasma levels. Consequently, factors must be present to alter breast tissue E2 levels independently of plasma concentrations. One such factor may be the local production of E2 in breast tissue through the enzyme aromatase, and the evidence supporting the expression of aromatase in breast tissue is also reviewed in this chapter. If correct, mutations or environmental factors enhancing aromatase activity might result in high tissue concentrations of E2 that would likely be sufficient to serve as substrates for CYP1B1, given its high affinity for E2. This concept, if verified experimentally, would provide plausibility to the hypothesis that sufficient E2 may be present in tissue for formation of catechol metabolites that are estrogenic and which, upon further oxidative metabolism, form genotoxic species at levels that may contribute to estrogen carcinogenesis.

Aromatase↗

PubMed2000

Roles of Fas and Fas ligand during mammary gland remodeling.

Mammary involution is associated with degeneration of the alveolar structure and programmed cell death of mammary epithelial cells. In this study, we evaluated the expression of Fas and Fas ligand (FasL) in the mammary gland tissue and their possible role in the induction of apoptosis of mammary cells. FasL-positive cells were observed in normal mammary epithelium from pregnant and lactating mice, but not in nonpregnant/virgin mouse mammary tissue. Fas expression was observed in epithelial and stromal cells in nonpregnant mice but was absent during pregnancy. At day 1 after weaning, high levels of both Fas and FasL proteins and caspase 3 were observed and coincided with the appearance of apoptotic cells in ducts and glands. During the same period, no apoptotic cells were found in the Fas-deficient (MRL/lpr) and FasL-deficient (C3H/gld) mice. Increase in Fas and FasL protein was demonstrated in human (MCF10A) and mouse (HC-11) mammary epithelial cells after incubation in hormone-deprived media, before apoptosis was detected. These results suggest that the Fas-FasL interaction plays an important role in the normal remodeling of mammary tissue. Furthermore, this autocrine induction of apoptosis may prevent accumulation of cells with mutations and subsequent neoplastic development. Failure of the Fas/FasL signal could contribute to tumor development.

Animals↗