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Calmon MS, Lemos FFB, Silva Luz M, Rocha Pinheiro SL, de Oliveira Silva LG, Correa Santos GL, Rocha GR, Freire de Melo F. Immune pathway through endometriosis to ovarian cancer. World J Clin Oncol 2024; 15:496-522. [PMID: 38689629 PMCID: PMC11056862 DOI: 10.5306/wjco.v15.i4.496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/29/2024] [Accepted: 03/18/2024] [Indexed: 04/22/2024] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disease, defined by the presence of functional endometrial tissue outside of the uterine cavity. This disease is one of the main gynecological diseases, affecting around 10%-15% women and girls of reproductive age, being a common gynecologic disorder. Although endometriosis is a benign disease, it shares several characteristics with invasive cancer. Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer, representing an earlier stage of neoplastic processes. This is particularly true for women with clear cell carcinoma, low-grade serous carcinoma and endometrioid. However, the carcinogenic pathways between both pathologies remain poorly understood. Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers (EAOCs) via pathways associated with oxidative stress, inflammation, and hyperestrogenism. This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis, specifically focusing on the complex relationship between the immune response to endometriosis and cancer, including the molecular mechanisms and their ramifications. Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.
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Affiliation(s)
- Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Giordano LA, Giordano MV, Célia Teixeira Gomes R, Dos Santos Simões R, Baracat MCP, Giordano MG, Ferreira-Filho ES, de Medeiros SF, Baracat EC, Soares-Júnior JM. Effects of clinical and metabolic variables and hormones on the expression of immune protein biomarkers in the endometrium of women with polycystic ovary syndrome and normal-cycling controls. Gynecol Endocrinol 2022; 38:508-515. [PMID: 35393909 DOI: 10.1080/09513590.2022.2061454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
BACKGROUND Women with polycystic ovary syndrome (PCOS) are at an elevated risk of endometrial cancer, which may be associated with the continuous proliferative state caused by the interaction between hormones and metabolic factors. OBJECTIVE To investigate the impact of hormones and metabolic factors in the proliferation and death of endometrium during the proliferative phase. METHODS Cross-sectional study with 11 women with PCOS and eight normal-cycling non-PCOS controls at the Federal University of the State of Rio de Janeiro from February 2011 to June 2019. Clinical, biochemical, and hormonal data were collected to analyze their influence on the expression of biomarkers related to the endometrial tissue breakdown. Hysteroscopy and endometrial biopsies were conducted, and the endometrial samples underwent immunohistochemistry for markers of apoptosis B-cell lymphoma 2 (BCL2), cleaved caspase-3 (CASP3), fas cell surface death receptor (FAS), FAS ligand (FASLG), BCL2 associated X (BAX), marker of proliferation Ki-67 (MKI67), and cell death using terminal deoxynucleotidyl transferase dUTP nick and labeling (TUNEL). RESULTS CASP3 and TUNEL expressions were lower in both stroma and endometrium gland of PCOS women than in controls. MKI67 and homeostasis indexes (BCL2/BAX; FASLG/FAS) in the endometrium of the PCOS group were significantly higher. Body mass index (BMI) values were positively correlated with the expression of MKI67 and MKI67/TUNEL ratio in the endometrial stroma compartment. Fasting insulin levels were positively correlated with the expression of BCL2, and DHEA-S levels were negatively correlated with the expression of CASP3 of women with PCOS. CONCLUSION BMI, insulin, and DHEA-S influence the endometrial homeostasis breakdown in PCOS in the endometrium stroma.
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Affiliation(s)
- Luiz Augusto Giordano
- Gynecology Department, Universidade Federal de São Paulo - UNIFESP, Sao Paulo, Brazil
- Gynecology Department, Universidade Federal do Estado do Rio de Janeiro - (UNIRIO), Rio de Janeiro, Brazil
| | - Mario Vicente Giordano
- Gynecology Department, Universidade Federal do Estado do Rio de Janeiro - (UNIRIO), Rio de Janeiro, Brazil
- Disciplina de Ginecologia do Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil
| | - Regina Célia Teixeira Gomes
- Disciplina de Ginecologia do Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil
| | - Ricardo Dos Santos Simões
- Disciplina de Ginecologia do Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil
| | - Maria Candida Pinheiro Baracat
- Disciplina de Ginecologia do Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil
| | - Mario Gáspare Giordano
- Gynecology Department, Universidade Federal do Estado do Rio de Janeiro - (UNIRIO), Rio de Janeiro, Brazil
- Disciplina de Ginecologia do Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil
| | - Edson Santos Ferreira-Filho
- Disciplina de Ginecologia do Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil
| | - Sebastião Freitas de Medeiros
- Department of Gynecology and Obstetrics, Medical School, Federal University of Mato Grosso, Cuiabá, Mato Grosso, Brazil
| | - Edmund Chada Baracat
- Disciplina de Ginecologia do Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil
| | - José Maria Soares-Júnior
- Disciplina de Ginecologia do Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil
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Zangouei AS, Hamidi AA, Rahimi HR, Saburi E, Mojarrad M, Moghbeli M. Chemokines as the critical factors during bladder cancer progression: an overview. Int Rev Immunol 2021; 40:344-358. [PMID: 33591855 DOI: 10.1080/08830185.2021.1877287] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Bladder cancer (BCa) is one of the most frequent urogenital malignancies which is mainly observed among men. There are various genetic and environmental risk factors associated with BCa progression. Transurethral endoscopic resection and open ablative surgery are the main treatment options for muscle invasive BCa. BCG therapy is also employed following the endoscopic resection to prevent tumor relapse. The tumor microenvironment is the main interaction site of tumor cells and immune system in which the immune cells are recruited via chemokines and chemokine receptors. In present review we summarized the main chemokines and chemokine receptors which have been associated with histopathological features of BCa patients in the world. This review highlights the chemokines and chemokine receptors as critical markers in early detection and therapeutic purposes among BCa patients and clarifies their molecular functions during BCa progression and metastasis.
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Affiliation(s)
- Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Abbas Hamidi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Saburi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Mojarrad
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Kolahdouz-Mohammadi R, Shidfar F, Khodaverdi S, Arablou T, Heidari S, Rashidi N, Delbandi AA. Resveratrol treatment reduces expression of MCP-1, IL-6, IL-8 and RANTES in endometriotic stromal cells. J Cell Mol Med 2020; 25:1116-1127. [PMID: 33325132 PMCID: PMC7812293 DOI: 10.1111/jcmm.16178] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 11/11/2020] [Accepted: 11/25/2020] [Indexed: 12/21/2022] Open
Abstract
Endometriosis is an inflammatory disease affecting reproductive‐aged women. Immunologic disturbance, as well as inflammation, have crucial roles in the pathogenesis of endometriosis. In this study, we evaluated the effects of resveratrol treatment on expression of monocyte chemotactic protein‐1 (MCP‐1), interleukin‐6 (IL‐6), IL‐8, and regulated upon activation, normal T cell expressed and secreted (RANTES) in endometrial stromal cells from patients with endometriosis compared with non‐endometriotic controls. Thirteen eutopic (EuESCs) and nine ectopic (EESCs) endometrial stromal cells from endometriotic patients as well as eleven endometrial stromal cells from non‐endometriotic controls (CESCs) were treated with resveratrol (100 μmol/L) or ethanol, and gene and/or protein expression of MCP‐1, IL‐6, IL‐8 and RANTES was examined at 6, 24 and 48 hours following treatment in the cells from all origins. Resveratrol treatment significantly reduced gene and protein expression of MCP‐1, IL‐6, and IL‐8 in EuESCs and EESCs compared with CESCs (P < .05‐.001, P < .05‐.001 and P < .05‐<.01, respectively), and this reduction was more noticeable in EESCs than EuESCs (P < .05‐<.001). Besides, resveratrol treatment significantly reduced RANTES protein expression in EESCs in all time intervals (P < .05). Resveratrol treatment significantly reduced the expression of MCP‐1, IL‐6, IL‐8 and RANTES in EESCs.
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Affiliation(s)
- Roya Kolahdouz-Mohammadi
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Farzad Shidfar
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Sepideh Khodaverdi
- Endometriosis Research Center, Iran University of Medical Science, Tehran, Iran
| | - Tahereh Arablou
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Sahel Heidari
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nesa Rashidi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Delbandi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
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Kawakita T, Kato T, Iwasa T, Erdenebayar O, Kadota Y, Kasai K, Yoshida K, Irahara M. Mental stress promotes the proliferation of endometriotic lesions in mice. Cytokine 2020; 135:155222. [PMID: 32768923 DOI: 10.1016/j.cyto.2020.155222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 07/02/2020] [Accepted: 07/23/2020] [Indexed: 10/23/2022]
Abstract
Endometriosis is a condition in which tissue similar to the womb lining begins to grow in other sites, such as the ovaries or fallopian tubes. Endometriosis can cause pelvic pain, adhesion formation, and infertility. Here, we investigated the relationship between deterioration of endometriosis and inflammation of intraperitoneal adipose tissue in mice. We created a mouse model of endometriosis, then subjected these mice to stress loading. In the experimental mice, we measured protein expression levels of prostaglandin-E2, monocyte chemoattractant protein-1, and tumor necrosis factor-α using ELISA kits. We used quantitative real-time polymerase chain reaction to measure mRNA expression levels of inflammation-related enzymes and cytokines in lesions and adipose tissues. This study sugest that endometriotic lesions may progress in the presence of psychological stress in the presence of endometriosis. In addition, inflammation of the adipose tissue around the uterus may be involved in the development of endometriosis. However, this needs further consideration. Reducing or avoiding stress as much as possible may prevent the progression of endometriosis.
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Affiliation(s)
- Takako Kawakita
- Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto cho, Tokushima, Japan.
| | - Takeshi Kato
- Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto cho, Tokushima, Japan
| | - Takeshi Iwasa
- Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto cho, Tokushima, Japan
| | - Otgontsetseg Erdenebayar
- Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto cho, Tokushima, Japan
| | - Yuri Kadota
- Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto cho, Tokushima, Japan
| | - Kana Kasai
- Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto cho, Tokushima, Japan
| | - Kanako Yoshida
- Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto cho, Tokushima, Japan
| | - Minoru Irahara
- Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto cho, Tokushima, Japan
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Cho YJ, Lee SH, Park JW, Han M, Park MJ, Han SJ. Dysfunctional signaling underlying endometriosis: current state of knowledge. J Mol Endocrinol 2018; 60:R97-R113. [PMID: 29330150 DOI: 10.1530/jme-17-0227] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 01/11/2018] [Indexed: 12/18/2022]
Abstract
Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity. It affects approximately 5-10% of women of reproductive age. Endometriosis is associated with dysmenorrhea, dyspareunia and, often, severe pelvic pain. In addition to pain, women with endometriosis often experience infertility. Defining the molecular etiology of endometriosis is a significant challenge for improving the quality of women's lives. Unfortunately, the pathophysiology of endometriosis is not well understood. Here, we summarize the potential causative factors of endometriosis in the following three categories: (1) dysregulation of immune cells in the peritoneal fluid and endometriotic lesions; (2) alteration of apoptotic signaling in retrograde menstrual tissue and cytotoxic T cells involved in endometriosis progression and (3) dysregulation of oxidative stress. Determining the molecular etiology of these dysregulated cellular signaling pathways should provide crucial clues for understanding initiation and progression of endometriosis. Moreover, improved understanding should suggest new molecular therapeutic targets that could improve the specificity of endometriosis treatments and reduce the side effects associated with current approaches.
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Affiliation(s)
- Yeon Jean Cho
- Department of Obstetrics and Gynecology, Dong-A University, College of Medicine, Busan, Republic of Korea
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Seung Hyun Lee
- Department of Obstetrics and Gynecology, Dong-A University, College of Medicine, Busan, Republic of Korea
| | - Jung Woo Park
- Department of Obstetrics and Gynecology, Dong-A University, College of Medicine, Busan, Republic of Korea
| | - Myoungseok Han
- Department of Obstetrics and Gynecology, Dong-A University, College of Medicine, Busan, Republic of Korea
| | - Mi Jin Park
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Sang Jun Han
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, USA
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Ahn SH, Khalaj K, Young SL, Lessey BA, Koti M, Tayade C. Immune-inflammation gene signatures in endometriosis patients. Fertil Steril 2016; 106:1420-1431.e7. [PMID: 27475412 DOI: 10.1016/j.fertnstert.2016.07.005] [Citation(s) in RCA: 120] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 05/31/2016] [Accepted: 07/06/2016] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To determine if the molecular profiles of endometriotic lesions contain informative measures of inflammation and immune dysfunction that may contribute to better understanding of the interplay between immune dysfunction and inflammation and their contribution to endometriosis pathogenesis. DESIGN Immune and inflammation transcriptomic analysis with the use of the Nanostring nCounter GX Human Immunology V2 platform (579 human immune and inflammation-related genes and 15 housekeeping genes). SETTING Academic university and teaching hospital. INTERVENTION(S) None. PATIENT(S) Stage III-IV endometriosis patients with infertility (n = 8) and fertile disease-free control women undergoing tubal ligation (n = 8). Menstrual stage was matched to secretory phase in all participants. MAIN OUTCOME MEASURE(S) Immune and inflammation transcriptomics quantification from ectopic endometriotic lesions and matched eutopic endometrium from patients. Endometria of fertile women served as control subjects. RESULT(S) Our results displayed endometriotic lesions as molecularly distinct entities compared with eutopic endometrium and endometrium of control samples; 396 out of 579 screened immune and inflammation-related genes were significantly different in ectopic tissues compared with control endometrium. Most importantly, eutopic endometrium of the patients displayed a unique molecular profile compared with the control endometrium (91/579 genes were significantly different), particularly of genes involved in regulation of cell apoptosis and decidualization. CONCLUSION(S) We characterize differential expression of immune-inflammation genes in endometriosis patients, and show molecular distinction of eutopic endometrium of patients compared with control fertile women.
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Affiliation(s)
- Soo Hyun Ahn
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Kasra Khalaj
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Steven L Young
- Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina
| | - Bruce A Lessey
- Department of Obstetrics and Gynecology, Greenville Health Systems, Greenville, South Carolina
| | - Madhuri Koti
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Chandrakant Tayade
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
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Ruiz LA, Báez-Vega PM, Ruiz A, Peterse DP, Monteiro JB, Bracero N, Beauchamp P, Fazleabas AT, Flores I. Dysregulation of Lysyl Oxidase Expression in Lesions and Endometrium of Women With Endometriosis. Reprod Sci 2015; 22:1496-508. [PMID: 25963914 PMCID: PMC5933196 DOI: 10.1177/1933719115585144] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
UNLABELLED Lysyl oxidases (LOXs) are enzymes involved in collagen deposition, extracellular membrane remodeling, and invasive/metastatic potential. Previous studies reveal an association of LOXs and endometriosis. We aimed to identify the mechanisms activated by upregulation of lysyl oxidases (LOX) in endometriotic cells and tissues. We hypothesized that LOX plays a role in endometriosis by promoting invasiveness and epithelial to mesenchymal transition (EMT). METHODS The LOX protein expression levels were measured by immunohistochemistry in lesions and endometrium on a tissue microarray (TMA) and in endometrial biopsies from patients and controls during the window of implantation (WOI). Estradiol regulation of LOX expression was determined by quantitative polymerase chain reaction (qPCR). Proliferation, invasion, and migration assays were performed in epithelial (endometrial epithelial cell), endometrial (human endometrial stromal cell), and endometriotic cell lines (ECL and 12Z). Pathway-focused multiplex qPCR was used to determine transcriptome changes due to LOX overexpression. RESULTS LOX protein was differentially expressed in ovarian versus peritoneal lesions. During WOI, LOX levels were higher in luminal epithelium of patients with endometriosis-associated infertility compared to controls. Invasive epithelial cell lines expressed higher levels of LOX than noninvasive ones. Transfection of LOX into noninvasive epithelial cells increased their migration in an LOX inhibitor-sensitive manner. Overexpression of LOX did not fully induce EMT but the expression of genes related to fibrosis and extracellular matrix remodeling were dysregulated. CONCLUSIONS This study documents that expression of LOX is differentially regulated in endometriotic lesions and endometrium. A role for LOX in mediating proliferation, migration, and invasion of endometrial and endometriotic cells was observed, which may be implicated in the establishment and progression of endometriotic lesions.
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Affiliation(s)
- Lynnette A Ruiz
- Department of Anatomy, Ponce Health Sciences University-School of Medicine & Ponce Research Institute, Ponce, PR, USA
| | - Perla M Báez-Vega
- Comprehensive Cancer Center, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, USA
| | - Abigail Ruiz
- Department of Microbiology, Ponce Health Sciences University-School of Medicine & Ponce Research Institute, Ponce, PR, USA
| | - Daniëlle P Peterse
- Department of Development and Regeneration, University Hospital Leuven, Leuven, Belgium
| | - Janice B Monteiro
- Department of Biochemistry, Ponce Health Sciences University- School of Medicine & Ponce Research Institute, Ponce, PR, USA
| | - Nabal Bracero
- Department of Ob-Gyn, University of Puerto Rico - Medical Sciences Campus, Genes Fertility Institute, San Juan, PR, USA
| | | | - Asgerally T Fazleabas
- Department of Ob-Gyn & Reproductive Biology, Michigan State University, Grand Rapids, MI, USA
| | - Idhaliz Flores
- Department of Microbiology, Department of Ob-Gyn, Ponce Health Sciences University-School of Medicine & Ponce Research Institute, Ponce, PR, USA
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Wu R, Zhou W, Chen S, Shi Y, Su L, Zhu M, Chen Q, Chen Q. Lipoxin A4 suppresses the development of endometriosis in an ALX receptor-dependent manner via the p38 MAPK pathway. Br J Pharmacol 2015; 171:4927-40. [PMID: 24923883 DOI: 10.1111/bph.12816] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Revised: 04/18/2014] [Accepted: 06/06/2014] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND AND PURPOSE Lipoxins can function as endogenous 'breaking signals' in inflammation and play important roles in the progression of endometriosis. In this study, we further investigated the molecular mechanism by which lipoxin A4 (LXA4 ) suppresses the development of endometriosis. EXPERIMENTAL APPROACH Primary endometriotic stromal cells (ESCs) were treated with IL-1β, or pre-incubated with LXA4 before incubation with IL-1β. The LXA4 receptor (ALX receptor) antagonist Boc-2 and gene-silencing approaches were used to study the involvement of the ALX receptor in anti-inflammatory signalling responses in ESCs. An animal model of endometriosis was induced in BALB/c mice by i.p. injection of an endometrium-rich fragment. KEY RESULTS Decreased levels of LXA4 and 15-LOX-2 expression but increased expression of AXL receptors were observed in endometriotic tissues. LXA4 inhibited the release of inflammatory factors and phosphorylation of p38 MAPK in IL-1β-induced ESCs, an effect mediated by ALX receptors. LXA4 inhibited the proliferation of ESCs, as indicated by reduced DNA replication, caused G0 /G1 phase cell cycle arrest and down-regulated the expression of proliferating cell nuclear antigen in ESCs. LXA4 also attenuated the invasive activity of ESCs mainly by suppressing the expression and activity of MMP-9. In vivo, we further confirmed that LXA4 could inhibit the progression of endometriosis by acting as an anti-inflammatory. CONCLUSIONS AND IMPLICATIONS LXA4 exerted anti-inflammatory, anti-proliferative and anti-invasive effects on endometriosis through a mechanism that involved down-regulating the activities of p38 MAPK, which was mediated by ALX receptors.
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Affiliation(s)
- Rongfeng Wu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
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Wang Y, Lin M, Weng H, Wang X, Yang L, Liu F. ENMD-1068, a protease-activated receptor 2 antagonist, inhibits the development of endometriosis in a mouse model. Am J Obstet Gynecol 2014; 210:531.e1-8. [PMID: 24495669 DOI: 10.1016/j.ajog.2014.01.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 12/11/2013] [Accepted: 01/28/2014] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Protease-activated receptor 2 plays an important role in the pathogenesis of endometriosis. We studied the effect of ENMD-1068, a protease-activated receptor 2 antagonist, on the development of endometriosis in a noninvasive fluorescent mouse model. STUDY DESIGN A red fluorescent protein-expressing xenograft model of human endometriosis was created in nude mice. After endometriosis induction, the mice were injected intraperitoneally with either 25 mg/kg or 50 mg/kg ENMD-1068 or with 200 μL of the vehicle control daily for 5 days. The endometriotic lesions that developed in the mice were then counted, measured, and collected. The lesions were assessed for the production of interleukin 6 and monocyte chemotactic protein-1 by enzyme-linked immunosorbent assays and evaluated for the activation of nuclear factor-κB and the expression of vascular endothelial growth factor by immunohistochemical analyses. Cell proliferation and apoptosis were assessed by immunohistochemistry for Ki-67 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, respectively. RESULTS ENMD-1068 dose-dependently inhibited the development of endometriotic lesions (P < .05) without apparent toxicity to various organs of the treated mice. Consistently, ENMD-1068 dose-dependently inhibited the expression of interleukin 6 and nuclear factor-κB (P < .05) and cell proliferation (P < .05) in the lesions, as well as increased the percentage of apoptotic cells (P < .05). ENMD-1068 reduced the levels of monocyte chemotactic protein-1 and vascular endothelial growth factor in the lesions (P < .05), but not in a dose-dependent manner. CONCLUSION Our study suggests that ENMD-1068 is effective in suppressing the growth of endometriosis, which might be attributed to the drug's antiangiogenic and antiinflammatory activities.
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Affiliation(s)
- Yifeng Wang
- Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Min Lin
- Department of Obstetrics and Gynecology, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Huinan Weng
- Department of Reproductive Center, GuangDong Women And Children Hospital, Guangzhou, China
| | - Xuefeng Wang
- Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Li Yang
- Department of Obstetrics and Gynecology, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Fenghua Liu
- Department of Reproductive Center, GuangDong Women And Children Hospital, Guangzhou, China.
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11
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Anand A, Gupta PK, Prabhakar S, Sharma S, Thakur K. Analysis of smoking and LPO in ALS. Neurochem Int 2014; 71:47-55. [DOI: 10.1016/j.neuint.2014.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 03/26/2014] [Accepted: 04/03/2014] [Indexed: 12/11/2022]
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Srivastava A, Sengupta J, Kriplani A, Roy KK, Ghosh D. Profiles of cytokines secreted by isolated human endometrial cells under the influence of chorionic gonadotropin during the window of embryo implantation. Reprod Biol Endocrinol 2013; 11:116. [PMID: 24345207 PMCID: PMC3878507 DOI: 10.1186/1477-7827-11-116] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 12/10/2013] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Several studies have indicated that human pre-implantation embryo-derived chorionic gonadotropin (hCG) may influence the implantation process by its action on human endometrial epithelial and stromal cells. Despite reports indicating that hCG acts on these cells to affect the production of several cytokines and growth factors (e.g., MIF, IGF-I, VEGF, LIF, IL-11, GMCSF, CXL10 and FGF2), our understanding of the integral influence of hCG on paracrine interactions between endometrial stromal and epithelial cells during implantation is very limited. METHODS In the present study, we examined the profile of 48 cytokines in the conditioned media of primary cell cultures of human implantation stage endometrium. Endometrial epithelial cells (group 1; n = 20), stromal cells (group 2; n = 20), and epithelial plus stromal cells (group 3; n = 20) obtained from mid-secretory stage endometrial samples (n = 60) were grown on collagen and exposed to different doses (0, 1, 10 and 100 IU/ml) of rhCG for 24 h in vitro. Immunochemical and qRT-PCR methods were used to determine cytokine profiles. Enrichment and process networks analyses were implemented using a list of cytokines showing differential secretion in response to hCG. RESULTS Under basal conditions, endometrial epithelial and stromal cells exhibited cell type-specific profiles of secreted cytokines. Administration of hCG (100 IU) resulted in significantly (P < 0.05) different cytokine secretion profiles indicative of macropinocytic transport (HGF, MCSF) in epithelial cells, signal transduction (CCL4, FGF2, IL-1b, IL-6, IL-17, VEGF) in stromal cells, and epithelial-mesenchymal transition (FGF2, HGF, IL-1b, TNF) in mixed cells. Overall, the administration of hCG affected cytokines involved in the immune response, chemotaxis, inflammatory changes, proliferation, cell adhesion and apoptosis. CONCLUSIONS CG can influence the function of the endometrium during blastocyst implantation via its differential action on endometrial epithelial and stromal cells. CG may also affect complex paracrine processes in the different endometrial cell types.
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Affiliation(s)
- Akhilesh Srivastava
- Department of Physiology, All India Institute of Medical Sciences, New Delhi, India
| | - Jayasree Sengupta
- Department of Physiology, All India Institute of Medical Sciences, New Delhi, India
- Present address: Department of Physiology, North DMC Medical College, Hindu Rao Hospital, New Delhi 110007, India
| | - Alka Kriplani
- Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, India
| | - Kallol K Roy
- Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, India
| | - Debabrata Ghosh
- Department of Physiology, All India Institute of Medical Sciences, New Delhi, India
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Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Hum Reprod Update 2013; 19:406-18. [PMID: 23539633 DOI: 10.1093/humupd/dmt010] [Citation(s) in RCA: 194] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The recruitment of immune cells by chemokines and the regulation of endometrial cell apoptosis are critical aspects of endometriosis biology. Here, we review the local (paracrine) and systemic hormone (endocrine) modulation of these two specific, but highly related phenomena. METHODS We searched Pubmed for items published in English between September 1991 and September 2011 and selected the studies evaluating the effects of hormones on chemokines or apoptosis in normal human endometrium and endometriosis. RESULTS Estradiol has proinflammatory and antiapoptotic effects in endometrial cells, and these effects appear to be exacerbated in women with endometriosis. In these women, physiological estradiol concentrations are able to induce an enhanced inflammatory response mediated by local chemokine production and to reinforce mechanisms of cell survival mediated by extracellular signal-regulated kinases and Bcl-2. The main effect of progestogens is to inhibit interleukin-8 and other chemokines in stromal cells from both eutopic and ectopic endometrium. Progesterone is also effective in inducing apoptosis in endometrial and endometriotic cells through the inhibition of Bcl-2 and nuclear factor-κB. CONCLUSIONS Estrogens and progestogens modulate chemotaxis and apoptosis in human endometrium and endometriotic cells and tissues. These endocrine and paracrine pathways are perturbed in women with endometriosis, contributing to inflammatory responses, abnormal tissue remodeling, therapeutic refractoriness and disease persistence. Ultimately, they promote adhesion formation and the clinical symptoms of pelvic pain and infertility. A more detailed understanding of the molecular mechanisms involved will offer new opportunities for novel pharmacological strategies to diagnose and treat endometriosis.
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Affiliation(s)
- Fernando M Reis
- Department of Obstetrics and Gynecology, University of Minas Gerais, Belo Horizonte, Brazil
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Autocrine CCL2 promotes cell migration and invasion via PKC activation and tyrosine phosphorylation of paxillin in bladder cancer cells. Cytokine 2012; 59:423-32. [PMID: 22617682 DOI: 10.1016/j.cyto.2012.04.017] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Revised: 03/27/2012] [Accepted: 04/11/2012] [Indexed: 12/20/2022]
Abstract
The amount of monocyte chemoattractant protein-1 (MCP-1/CCL2) produced by a transitional cell carcinoma is directly correlated with high recurrence and poor prognosis in bladder cancer. However, the mechanisms underlying the effects of CCL2 on tumor progression remain unexplored. To investigate the role played by CCL2, we examined cell migration in various bladder cancer cell lines. We found that high-grade cancer cells expressing high levels of CCL2 showed more migration activity than low-grade bladder cancer cells expressing low levels of the chemokine. Although the activation of CCL2/CCR2 signals did not appreciably affect cell growth, it mediated cell migration and invasion via the activation of protein kinase C and phosphorylation of tyrosine in paxillin. Blocking CCL2 and CCR2 with small hairpin RNA (shCCL2) or a specific inhibitor reduced CCL2/CCR2-mediated cell migration. The antagonist of CCR2 promoted the survival of mice bearing MBT2 bladder cancer cells, and CCL2-depleted cells showed low tumorigenicity compared with shGFP cells. In addition to observing high-levels of CCL2 in high-grade human bladder cancer cells, we showed that the CCL2/CCR2 signaling pathway mediated migratory and invasive activity, whereas blocking the pathway decreased migration and invasion. In conclusion, high levels of CCL2 expressed in bladder cancer mediates tumor invasion and is involved with advanced tumorigenesis. Our findings suggest that this CCL2/CCR2 pathway is a potential candidate for the attenuation of bladder cancer metastases.
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Li MQ, Li HP, Meng YH, Wang XQ, Zhu XY, Mei J, Li DJ. Chemokine CCL2 enhances survival and invasiveness of endometrial stromal cells in an autocrine manner by activating Akt and MAPK/Erk1/2 signal pathway. Fertil Steril 2012; 97:919-29. [DOI: 10.1016/j.fertnstert.2011.12.049] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2011] [Revised: 12/14/2011] [Accepted: 12/28/2011] [Indexed: 10/14/2022]
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Jana S, Paul S, Swarnakar S. Curcumin as anti-endometriotic agent: implication of MMP-3 and intrinsic apoptotic pathway. Biochem Pharmacol 2011; 83:797-804. [PMID: 22227273 DOI: 10.1016/j.bcp.2011.12.030] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Revised: 12/12/2011] [Accepted: 12/20/2011] [Indexed: 12/20/2022]
Abstract
The disease of reproductive women, endometriosis represents implantation of functional endometrial glands outside uterine cavity. This invasive disorder is associated with dysregulation of matrix metalloproteases (MMP)s and extracellular matrix (ECM) remodeling. In this study, we investigated the role of MMP-3 on apoptosis during endometriosis. We also checked whether curcumin has potency to regress endometriosis by modulating MMP-3 and apoptotic pathway. Mouse model of endometriosis was designed by intraperitoneal inoculation of endometrial tissues to syngeneic female BALB/c. At 15th day, stable endometriotic developments were observed with increased MMP-3 expression. TUNEL positive cells were also found with endometriotic progression, which might resulted from destruction of local immune cells. We speculate that increased MMP-3 activity might be involved in the Fas mediated apoptosis. Curcumin treatment regressed endometriosis by inhibiting NFκB translocation and MMP-3 expression. It also accelerated apoptosis in endometriomas predominantly via cytochrome-c mediated mitochondrial pathway. Involvement of mitochondria in apoptosis was further confirmed by atomic force microscopy (AFM). These results were also supported by our therapeutic study, where curcumin induced apoptosis both by p53 dependent and independent manner, while celecoxib followed only p53 independent pathway. Altogether, our study establishes the novel role of curcumin as a potent anti-endometriotic compound.
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Affiliation(s)
- Sayantan Jana
- Drug Development Diagnostics & Biotechnology Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India
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Dewals BG, Vanderplasschen A. Malignant catarrhal fever induced by Alcelaphine herpesvirus 1 is characterized by an expansion of activated CD3+CD8+CD4- T cells expressing a cytotoxic phenotype in both lymphoid and non-lymphoid tissues. Vet Res 2011; 42:95. [PMID: 21859474 PMCID: PMC3166908 DOI: 10.1186/1297-9716-42-95] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Accepted: 08/22/2011] [Indexed: 11/10/2022] Open
Abstract
Alcelaphine herpesvirus 1 (AlHV-1) is carried by wildebeest asymptomatically. It causes a fatal lymphoproliferative disease named wildebeest-derived malignant catarrhal fever (WD-MCF) when cross-species transmitted to a variety of susceptible species of the Artiodactyla order. WD-MCF can be reproduced experimentally in rabbits. In a previous report, we demonstrated that WD-MCF induced by AlHV-1 is associated with a severe proliferation of CD8(+) T cells in the lymphoid tissues. Here, we further studied the mononuclear leukocytic populations in both the lymphoid (throughout the infection and at time of euthanasia) and non-lymphoid (at time of euthanasia) organs during WD-MCF induced experimentally in rabbits. To reach that goal, we performed multi-colour flow cytometry stainings. The results obtained demonstrate that the development of WD-MCF correlates in peripheral blood with a severe increase of CD8(+) cell percentages; and that CD3(+)CD8(+)CD4(-) T cells were the predominant cell type in both lymphoid and non-lymphoid organs at time of euthanasia. Further characterization of the mononuclear leukocytes isolated from both lymphoid and non-lymphoid tissues revealed that the CD8(+) T cells express high levels of the activation markers CD25 and CD44, produce high amount of gamma-interferon (IFN-γ) and perforin, and showed a reduction of interleukin-2 (IL-2) gene expression. These data demonstrate that the development of WD-MCF is associated with the expansion and infiltration of activated and cytotoxic CD3(+)CD8(+)CD4(-) T cells secreting high amount of IFN-γ but low IL-2.
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Affiliation(s)
- Benjamin G Dewals
- Department of Infectious and Parasitic Diseases, Immunology-Vaccinology (B43b), Faculty of Veterinary Medicine, University of Liège, B-4000 Liège, Belgium.
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Osuga Y, Koga K, Hirota Y, Hirata T, Yoshino O, Taketani Y. Lymphocytes in Endometriosis. Am J Reprod Immunol 2010; 65:1-10. [DOI: 10.1111/j.1600-0897.2010.00887.x] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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Walker CG, Meier S, Littlejohn MD, Lehnert K, Roche JR, Mitchell MD. Modulation of the maternal immune system by the pre-implantation embryo. BMC Genomics 2010; 11:474. [PMID: 20707927 PMCID: PMC3091670 DOI: 10.1186/1471-2164-11-474] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 08/13/2010] [Indexed: 11/21/2022] Open
Abstract
Background A large proportion of pregnancy losses occur during the pre-implantation period, when the developing embryo is elongating rapidly and signalling its presence to the maternal system. The molecular mechanisms that prevent luteolysis and support embryo survival within the maternal environment are not well understood. To gain a more complete picture of these molecular events, genome-wide transcriptional profiles of reproductive day 17 endometrial tissue were determined in pregnant and cyclic Holstein-Friesian dairy cattle. Results Microarray analyses revealed 1,839 and 1,189 differentially expressed transcripts between pregnant and cyclic animals (with ≥ 1.5 fold change in expression; P-value < 0.05, MTC Benjamini-Hochberg) in caruncular and intercaruncular endometrium respectively. Gene ontology and biological pathway analysis of differentially expressed genes revealed enrichment for genes involved in interferon signalling and modulation of the immune response in pregnant animals. Conclusion The maternal immune system actively surveys the uterine environment during early pregnancy. The embryo modulates this response inducing the expression of endometrial molecules that suppress the immune response and promote maternal tolerance to the embryo. During this period of local immune suppression, genes of the innate immune response (in particular, antimicrobial genes) may function to protect the uterus against infection.
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Chen QH, Zhou WD, Su ZY, Huang QS, Jiang JN, Chen QX. Change of proinflammatory cytokines follows certain patterns after induction of endometriosis in a mouse model. Fertil Steril 2009; 93:1448-54. [PMID: 19342044 DOI: 10.1016/j.fertnstert.2009.02.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2008] [Revised: 01/21/2009] [Accepted: 02/05/2009] [Indexed: 10/21/2022]
Abstract
OBJECTIVE To examine the change in proinflammatory cytokines in the pathologic processes of endometriosis in mice. DESIGN A dynamic study on a murine model of endometriosis. SETTING Medical school. ANIMAL(S) Female BALB/c mice. INTERVENTION(S) Endometriosis was induced by injecting endometrial fragments of syngenic mice into the peritoneal cavity of model mice; in control group, phosphate-buffered saline instead of fragments was injected. The peritoneal fluid and the endometriotic lesions were harvested 1 to 21 days after the induction. MAIN OUTCOME MEASURE(S) The endometriotic lesions were weighed, the gene and protein levels of some proinflammatory cytokines, including interleukin 1beta, tumor necrosis factor alpha, vascular endothelial growth factor, and monocyte chemoattractant protein 1, were determined by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULT(S) The levels of these cytokines reached the first peak on the first day and no endometriotic lesions were found. The lesions began to appear on the second day, presenting red color during the initial 6 days, and then they turned dark-red, brown, or bluish. The adhesion took place on the 9th day, and all the lesions evolved into white or transparent cysts on the 15th day. Corresponding to these changes, the second and the third peaks were identified during the 3rd-6th day and the 12th-15th day, respectively. CONCLUSION(S) The change pattern of cytokines over time might bear some relationship with the development and progression of the endometriosis.
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Affiliation(s)
- Qiong-Hua Chen
- Department of Obstetrics and Gynecology, Xiamen First Hospital, affiliated with Fujian Medical University, Xiamen, People's Republic of China
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Umezawa M, Sakata C, Tanaka N, Kudo S, Tabata M, Takeda K, Ihara T, Sugamata M. Cytokine and chemokine expression in a rat endometriosis is similar to that in human endometriosis. Cytokine 2008; 43:105-9. [PMID: 18595729 DOI: 10.1016/j.cyto.2008.04.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2008] [Revised: 04/02/2008] [Accepted: 04/29/2008] [Indexed: 11/25/2022]
Abstract
The pathogenesis of endometriosis, a gynecologic disorder associated with infertility, appears to involve immune responses. However, the details involved have not been clarified. In this study, we analyzed expression levels of interleukin (IL)-6, IL-10, monocyte chemoattractant protein-1, eosinophil chemotactic protein, macrophage inflammatory protein-1alpha, and regulated on activation normal T cell expressed and secreted (RANTES) and CC chemokine receptor 1 in endometriotic lesions in a rat model in which endometrium is autotransplanted onto peritoneal tissue and found that they were remarkably increased, while those of IL-2, IL-4, and interferon-gamma were not. These results were obtained in a rat model induced by autologous, not allogeneic, transplantation of endometrial epithelium to the peritoneum. Expression of these factors is consistent with that of endometriosis in humans. Therefore, this model may be useful in the investigation of the pathogenesis and treatment of endometriosis.
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Affiliation(s)
- Masakazu Umezawa
- Department of Pathology, Tochigi Institute of Clinical Pathology, Tochigi 329-0112, Japan.
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Bredhult C, Sahlin L, Olovsson M. Gene expression analysis of human endometrial endothelial cells exposed to op'-DDT. Mol Hum Reprod 2008; 14:97-106. [PMID: 18204070 DOI: 10.1093/molehr/gam091] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
The endocrine disrupting chemical o, p'-dichlorodiphenyltrichloroethane (DDT) can affect reproductive organs, tissues and cells in several species. Treatment of human endometrial endothelial cells (HEECs) with 50 microM o,p'-DDT decreased their proliferation compared with the control. Microarray analyses revealed that o,p'-DDT affected biological processes such as the cell cycle, cell division, defence response and lipid and steroid metabolism, in cellular components such as the plasma membrane and chromosomes, with molecular functions involved in signalling, receptor and cytokine activity, confirming the results of the proliferation assay. Expression of five of the most differentially expressed genes identified in the microarray analysis was verified by real-time quantitative reverse transcription polymerase chain reaction in five HEEC cultures obtained from women in the proliferative phase and in five cultures obtained from women in the secretory phase of the menstrual cycle after treatment with o,p'-DDT. The present study supports our previous findings of decreased proliferation and increased cell death in response to o,p'-DDT and may offer important clues to the mechanisms of action of o,p'-DDT.
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Affiliation(s)
- C Bredhult
- Department of Women's and Children's Health, Uppsala University, SE-751 85 Uppsala, Sweden
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