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Immunolocalization of Estrogen Receptor Α and Β in Gastric Epithelium and Enteric Neurons

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Immunolocalization of Estrogen Receptor Α and Β in Gastric Epithelium and Enteric Neurons 65 Immunolocalization of estrogen receptor and in gastric epithelium and enteric neurons M Campbell-Thompson, K K Reyher and L B Wilkinson Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610–0267, USA (Requests for offprints should be addressed to M Campbell-Thompson, Box 100275, Department of Pathology, Immunology, and Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610, USA; Email: [email protected]fl.edu) Abstract A sexual dimorphism in gastric acid secretion has been cytoplasm, with specific punctate staining for ER in cell known for many years, with women secreting less acid bodies and fibers. These studies are the first to show (40%) than men. The mechanisms mediating this sex differences between ER and ER proteins in the epi- difference are unknown, but a role for estrogens is thelial cellular distribution in the fundus and antrum and suggested from animal models. Two estrogen receptor to detect co-expression in enteric neurons. These results (ER) subtypes, ER and ER, mediate genomic effects of suggest that estrogens may inhibit gastric acid secretion via estrogens, and mRNA for both subtypes has been detected genomic effects in fundic parietal cells through either ER in the rat stomach. The objective of this study was to subtype and in antral neuroendocrine cells via ER. determine the cellular distribution of ER and ER Moreover, co-expression of ER and ER in enteric proteins in the rat stomach. ER and ER proteins were neurons indicates that estrogenic effects could also be detected in nuclei of fundic parietal cells and epithelial mediated through neurogenic reflexes. Our findings imply cells in the progenitor zone. In the antrum, several cells that direct regulation of multiple cell types by estrogens were immunoreactive for ER in regions containing stem may contribute to the modulation of gastric functions and neuroendocrine cell types but ER protein was not that have been recognized during the estrous cycle and detected in antral glands. Both ER and ER proteins between the sexes. were expressed in enteric neurons within the nucleus and Journal of Endocrinology (2001) 171, 65–73 Introduction However, there are major differences between ER and ER in their tissue distribution, the phenotype of the Gastric acid secretion has a significant role in the corresponding knockout mice, and their ligand-dependent integrated responses to digestion of a meal. A striking transcriptional activities (Barkhem et al. 1998). For sexual dimorphism in gastric acid secretion has been example, 17-estradiol can stimulate transcriptional known for many years with women secreting significantly activity at an estrogen response element via either ER or less acid (40%) than men (Feldman et al. 1983, Prewett ER, yet can activate an AP-1 element only via ER et al. 1991). Reciprocal changes in gastric acid secretion (Paech et al. 1997). Tamoxifen and raloxifene, selective versus serum estradiol concentrations were reported dur- estrogen receptor modulators, stimulate AP-1 activity ing the menstrual cycle (Sakaguchi et al. 1991). In rats, through ER, yet do not activate gene transcription via basal gastric acid output is similar in females and males, ER or ER at an ERE. These interactions are further whereas histamine- and pentagastrin-stimulated gastric compounded by dimerization of ER as either homodimers acid output can be decreased by 17-estradiol admin- (/, /) or heterodimers (/) (Cowley et al. 1997, istration (Omole 1972, Limlomwongse & Piyachaturawat Pace et al. 1997). Cell-specific gene regulation is 1982, Aguwa 1984, Adeniyi 1991, Girma et al. 1997). also dependent on differential expression of certain ER At least two estrogen receptor (ER) subtypes, ER and coactivators and corepressors. Studies in mice with gene ER, mediate the genomic actions of estrogens (reviewed deletions for ER and ER have determined that ER is in Gustafsson 1999, Muramatsu & Inoue 2000). ER and critical for fertility and bone density in both sexes, whereas ER share homologous regions in the DNA and ligand ER has critical roles in follicular development in females binding domains (96% and 58% amino acid and possibly in prostate and bladder development in males homology respectively). These domains confer similar (Korach 2000). These findings underscore the complexity binding affinities for transcriptional activation of estrogen and diversity of estrogenic effects and the mechanisms response elements (ERE) and estradiol respectively. involved and demonstrate the necessity for knowledge of Journal of Endocrinology (2001) 171, 65–73 Online version via http://www.endocrinology.org 0022–0795/01/0171–065 2001 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 06:18:56AM via free access 66 M CAMPBELL-THOMPSON and others · Gastric ER and ER expression cellular distribution of the ER subtypes in each target For serum gastrin analysis, venous blood was obtained tissue. by cardiac puncture and stored on ice for 30 min. Samples We reported that ER and ER mRNA were ex- were spun at 3000 g and serum collected and stored at pressed in the epithelium of the rat upper gastro- 75 C. Samples were analyzed in triplicate in a single intestinal (GI) tract and that ER mRNA was expressed assay using RIA methods established in the laboratory in greater abundance than ER (Campbell-Thompson (McGuigan & Wolfe 1982). Human gastrin-17 was 1997). Similar findings were reported in human intestinal used as a standard and results were expressed as pg/ml tissues, and ER mRNA was localized throughout the GI (sensitivity 10 pg/ml). mucosa (Brandenberger et al. 1997, Enmark et al. 1997). To date, immunolocalization of ER has been studied in Tissue preparation the stomach because ER antibodies have only recently become available. However, studies have been conflicting For immunohistochemistry and in situ hybridization, rats regarding ER expression, with either low concentrations were fasted overnight with free access to water and of ER protein detected in normal human gastric mucosa anesthetized with sodium pentobarbital (60 mg/kg i.p.) (Cameron et al. 1992, Ciocca & Vargus Roig 1995) or a between 0900 and 1100 h, to avoid diurnal variation. Rats lack of expression (Rio & Chambon 1990, Kojima et al. were perfused through the abdominal aorta with Tyrodes’s ff 1991). bu er and 2% paraformaldehyde–lysine–periodate fixative The specific mechanisms by which estrogens may alter (PLP) (McLean & Nakane 1974). Stomach and uterus gastric acid secretion are unknown. Direct effects on were dissected and mesentery and fat removed. The gastric epithelial cells and secondary neuroendocrine stomach was opened along the greater curvature and ff ff interactions regulate secretion rates. We propose that contents rinsed o with phosphate bu er (PBS, 10 mM estrogens acting via nuclear ER directly regulate gastric KPO4, 150 mM NaCl, pH 7·4). Tissues were stored in parietal cell function. The aims of the present study were fixative overnight at 4 C. Full-thickness sections of to determine the cellular distribution of ER and ER stomach, including proximal fundus and distal antrum, and ffi genes in the gastric epithelium and to determine the uterine horn were embedded in a single para n block for effects of chronic 17-estradiol administration on gastric each rat. Sections 5 µm thick were placed on Probe-on- acid secretion and gastric ER subtype distribution. Plus slides (Fisher, Pittsburgh, PA, USA) and stored at 20 C. For RNA analysis, rats were killed and uteri were removed and drained of fluid before freezing and Materials and Methods weighing. Uterine total RNA was analyzed as previously reported (Campbell-Thompson 1997). Animals and procedures Young adult female Sprague–Dawley rats (210–270 g, Antibodies n=31, Harlan, Indianapolis, IN, USA) were used. All The specificity of the polyclonal ER and ER antibodies experiments were approved by the Institutional Animal (Table 1) was verified by immunolocalization in the uterus Care Committee of the University of Florida using pro- which has been well characterized (Saunders et al. 1997, cedures of the NIH Guide for the Care and Use of Weihua et al. 2000). To detect ER, we used primarily Laboratory Animals. Rats had ad libitum access to rat chow antisera ER-21 and ER-715, which have no counterparts and water and were housed individually in wire-bottom in ER (Kuiper et al. 1996), and have been extensively cages (14-h light:10-h darkness cycle). Rats were accli- characterized (Table 1). To detect ER, we used two mated to conditions for 7 days and divided into groups of antibodies from Affinity BioReagents (Golden, CO, USA) ovariectomized and intact females. Bilateral ovariectomy (Table 1). PA1–311 was directed against a synthetic was performed under general anesthesia using sterile peptide corresponding to the N-terminal amino acids of techniques. Rats were allowed to recover from surgery for rat ER. This peptide has three of 18 (19%) amino acids 5 days and then received daily s.c. injections of corn oil in common with rat ER. PA1–310 was generated against vehicle (Ovx) or 17-estradiol (Ovx-E2; 1, 10, 20, 50 and amino acids in the C-terminal region of the rat ER and 100 µg/kg) for 1 week. Ovx and Ovx-E2 rats were has only 6% amino acid homology with rat ER.Both randomly assigned into pairs. The daily food consumption ER antibodies were affinity-purified by column chroma- of each Ovx-E2 rat was calculated and the same amount of tography and their immunolocalization reported in other food was given to the Ovx rat. Without pair-feeding, tissues (Table 1). Ovx-E2 rats (d10 µg/kg) ate 3–8 g food/day less than Ovx controls (data from four pairs monitored for 1 week). Immunohistochemistry Body weights were determined at arrival, surgery and end of the studies. For immunolocalization and in situ Tissue sections were heated at 55 C for 30 min and hybridization studies, Ovx-E2 rats received 20 µg/kg immediately dewaxed and hydrated using xylenes, graded 17-estradiol.
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