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Identifier 000382409
Title Study of the expression,the regulation and the biological role of the corticotropin releasing hormone (CRH) in endometriosis
Alternative Title Μελέτη της έκφρασης,της ρύθμισης και του βιολογικού ρόλου του εκλυτικού παράγοντα της κορτικοτροπίνης (CRH ,corticotropin releasing hormone)στην ενδομητρίωση
Author Βεργετάκη, Αικατερίνη
Thesis advisor Μακρυγιαννάκης, Αντώνιος
Reviewer Γραβάνης, Αχιλλέας
Τσατσάνης, Χρήστος
Παπακωνσταντή, Ευαγγελία
Ρελάκης, Κωνσταντίνος
Σταθόπουλος, Ευστάθιος
Δημητρίου, Ελένη
Abstract Endometriosis is one of the most important benign chronic diseases affecting the 6-10% of women of reproductive age, being mainly associated with pelvic pain, adhesion formation and infertility. Endometriosis is characterised by the ectopic presence of endometrial stroma and epithelium. Endometriosis has been proven to be both an estrogen-dependent and a chronic inflammatory disease. In that context, endocrine/paracrine influences and immunological aspects have been investigated. Thus, several growth factors, cytokines, immune cells and hormones in eutopic and ectopic endometrium, are considered to be involved in the pathophysiology of endometriosis-related infertility. CRH (Corticotropin Releasing Hormone) is a 41-amino acid neuropeptide, synthesised in the hypothalamus, regulating the hypothalamus-pituitary-adrenal axis and its expression and biological functions are mediated by its membrane receptors, CRH-R1 (α, β, γ, c-h) and CRH-R2 (α, β, γ). CRH receptors are also activated by other endogenous agonists, such as urocortin (UCN), which is a 40-amino acid peptide belonging to the corticotropin-releasing hormone family and is structurally related to CRH. Apart from the central nervous system, CRH and its receptors are expressed in several sites of the female reproductive system, including the endometrial glands, decidualized stroma, trophoblast, syncytiotrophoblast and placental decidua. CRH and UCN are secreted at inflammatory sites, acting as proinflammatory factors. Reproductive CRH has been shown to serve as an autocrine and paracrine modulator and to participate in decidualization, embryo implantation and maintenance of human pregnancy. In addition, CRH and UCN mRNA have been found to be expressed by endometriotic cells, while endometriotic lesions show a strongly positive staining reaction for CRH and UCN. The expression and function of CRH and UCN have also been found to be impaired in eutopic endometrium of women with endometriosis. These data suggest a crucial role of CRH and UCN in pathogenesis of endometriosis. However, the relative expression of CRH, UCN and their receptors in eutopic and ectopic endometrium of endometriotic women and in eutopic endometrium of healthy women and women with endometriosis have never been investigated. Additionally, CRH receptors and in particular their subtypes have never been identified in endometriotic lesions. In this current study, the relative expression levels of these molecules in eutopic and ectopic endometrium of endometriotic and healthy women have been investigated, indicating a potential role of CRH receptors in infertility profile of endometriotic women. As a result it is shown, in this current study, that CRHR1 and CRHR2 are expressed in endometriotic tissue and their expression levels are higher in eutopic endometrium of women with endometriosis compared to their expression levels in eutopic endometrium of healthy women. Moreover, CRH, UCN CRHR1 and CRHR2 have been found to be more abundantly expressed in ectopic rather than eutopic endometrium of the same endometriotic women. As endometriosis is characterized by the release of several growth factors and expression of integrins, cadherins and lectins that regulate cell migration, invasion, angiogenesis, immune functions and apoptosis, galectins, which are characterized as members of a large family of animal lectins which bind b- 18 galactoside should play an important role in this inflammatory disease. Galectins have strongly been implicated in inflammation and may be useful targets for anti-inflammatory therapy. As far as the immune system concerned, galectins are found in activated macrophages and B cells. They play a vital role in T cell homeostasis and survival. Galectin-1 plays a major role in initiation, activation and resolution of inflammatory responses and can act as a pro-inflammatory or an anti-inflammatory cytokine. Galectin-1 induces inhibition of cell growth and cell-cycle arrest and promotes the apoptosis of activated immune cells. Galectin-1 has been found to be expressed in human endometrium and decidua apart from other tissues but it has not been investigated in endometriotic tissue and in this current study it was a motivation in order to examine the galectin-1 expression in eutopic endometrium and in endometriotic tissue and compare it to that in eutopic endometrium of endometriotic women and healthy women. So, as a result, in this study, it is shown that galectin-1 shows much higher expression levels at the late secretory phase of eutopic endometrium and its expression levels are higher in ectopic endometrium compared to eutopic endometrium of endometriotic and healthy women. Moreover, the evaluation of its regulation by CRH, UCN and FasL was performed in Ishikawa cell line and peripheral macrophages as to possibly set new light concerning galectin-1 inflammatory role in endometriosis and infertility. So, as a result, it is shown that CRH, UCN and CSF-1 upregulate galectin-1 expression in both the cells types and the upregulative effect of the former one is mediated by CRHR1. Colony stimulating factor- 1 is a secreted cytokine, characterized as a haematopoietic growth factor which influences hematopoietic stem cells to differentiate into macrophages or other related cell types. Macrophages and other cells of the female reproductive tract are also regulated by locally produced CSF-1. CSF-1 plays an important role in placental growth and differentiation. As endometriosis is an inflammatory disease, there are several cytokines and growth factors that are implicated in this immune-disequilibrium status. As secretory cells, monocytes and macrophages are vital to the regulation of immune responses and the development of inflammation. These cytokines are produced by peritoneal macrophages, lymphocytes, mesothelial cells and endometriosis implants. Furthermore, women with endometriosis are characterised by increased number of peritoneal macrophages and by increased expression of CSF-1 compared to healthy ones. So, it was of quite interest, to examine the possible co-localization of galectin-1 and macrophage expression in endometriotic tissue, the CSF-1 expression in eutopic and ectopic endometrium of endometriotic and healthy women and how CSF-1 is regulated by CRH, UCN and CSF-1 in Ishikawa cell line and peripheral macrophages. In this current study, it is shown that there is a co-localization of macrophages and galectin-1 in ectopic sites. CSF-1 has been found to be much more highly expressed in ectopic endometrium compared to eutopic endometrium of endometriotic and healthy women. CRH, UCN and exogenously added CSF-1 have been shown to upregulate CSF-1 expression in Ishikawa cell line and macrophages and the upregulative effect of the former one is mediated by CRHR1. Fas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system. FasL is expressed on the surface of fetal cytotrophoblasts as well as 19 maternal decidual cells of the placenta and maternal endometrium. Abnormalities of maternal immune tolerance to the fetal semi-allograft and vise versa have been implicated in several pregnancy malfunctions such as recurrent early miscarriage, pre-eclampsia and eclampsia. CRH produced locally by decidual cells and extravillous trophoblasts acts in an autocrine/paracrine fashion, through CRH-R1, to stimulate FasL expression and to potentiate the ability of these cells to cause apoptosis of activated maternal T lymphocytes in order proper decidualization to occur. As FasL is implicated in inflammatory processes, it has been found that Fas is expressed randomly in both eutopic and ectopic endometrial tissues. Higher expression of FasL by endometriotic tissues contributes to their survival and the development of endometriosis. It has been suggested that the levels of soluble/active FasL are higher in serum and peritoneal fluid in women with moderate to severe endometriosis than in women with early‐stage disease or in healthy women. Consequently, ectopic endometrial cells escaping from immune surveillance in the peritoneal cavity of women with endometriosis may contribute to the maintenance of the disease, so it was of high importance to study how FasL is regulated by stress neuropeptides such as CRH and UCN and by an important macrophage factor such as CSF-1, in Ishikawa cell line and peripheral macrophages. As a result, in this study it is shown that CRH, UCN and CSF-1 upregulate FasL expression in both the cell types and the upregulative effect of the former one is mediated by CRHR1. In conclusion, the findings of this current study point to a new inflammatory- modulatory pathway in which CRH, UCN, CRHR1 and CRHR2 are involved acting by an autocrine/paracrine pathway in eutopic and ectopic endometrium potentially affecting the pathogenesis of endometriosis and the infertility profile of endometriotic women. These results suggest that a new therapeutic intervention could potentially based on blockage of CRH, UCN and their receptors leading to the improvement of the quality of endometriotic women’s life. Furthermore, it is proposed that galectin-1 could play a vital role in the pathogenesis of the disease. In addition, CRH, UCN and CSF-1 have been found to upregulate galectin-1, CSF-1 and FasL expression in Ishikawa cell line and macrophages. As all the peptides causing these upregulative effects and the molecules that are regulated by them are implicated in inflammation procedures such as endometriosis and in reproductive functions such as decidualization and implantation, these results could possibly set new light to the immune disequilibrium of endometriosis and the infertility profile of endometriotic women. Finally, this study results suggest that the potential use of antalarmin could be further considered in accessing the immune disequilibrium noticed in eutopic and ectopic endometrium of women with endometriosis.
Language Greek
Subject CSF-1
Endometriosis
FasL
Fertility
Galectin-1
Inflammation
UCN
Ενδομητρίωση
Υπογονιμότητα
Φλεγμωνή
Issue date 2013-07-16
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/d/f/3/metadata-dlib-1391752831-15634-9768.tkl Bookmark and Share
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