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Zhang Q, Yang D, Han X, Ren Y, Fan Y, Zhang C, Sun L, Ye T, Wang Q, Ban Y, Cao Y, Zou H, Zhang Z. Alarmins and their pivotal role in the pathogenesis of spontaneous abortion: insights for therapeutic intervention. Eur J Med Res 2024; 29:640. [PMID: 39741354 DOI: 10.1186/s40001-024-02236-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/06/2024] [Accepted: 12/18/2024] [Indexed: 01/02/2025] Open
Abstract
Alarmins are a class of molecules released when affected cells damaged or undergo apoptosis. They contain various chemotactic and immunomodulatory proteins or peptides. These molecules regulate the immune response by interacting with pattern recognition receptors (PRRs) and play important roles in inflammatory response, tissue repair, infection defense, and cancer treatment. Spontaneous abortion (SA) is a common pregnancy-related disease, and its pathogenesis has been puzzling clinicians, so it needs to be further studied. In this paper, we first reviewed the research status of various alarmins and SA, focusing on the role of high mobility box 1 (HMGB1), interleukin33 (IL-33), interleukin1β (IL-1β) and S-100 protein (S100 protein) in immune response, inflammation, embryonic development and abortion. Subsequently, this paper summarized the effect of alarmins on pregnancy outcome by influencing angiogenesis-related factors. Finally, from the perspective of aseptic inflammation, the pro-inflammatory signaling pathways involved in various alarmins and their targeted drugs were reviewed. By focusing on specific molecules in alarmins and their receptors and signaling pathways, we can more accurately conduct drug research and development. The purpose of this review is to explore the role of alarmins in SA, and provide important references for early detection of abortion risk, revealing the disease mechanism, developing new therapies and improving the prognosis of patients.
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Affiliation(s)
- Qiqi Zhang
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei, Anhui, China
| | - Dandan Yang
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei, Anhui, China
| | - Xingxing Han
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, Hefei, Anhui, China
| | - Yu Ren
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
- Anhui Province Key Laboratory of Reproductive Disorders and Obstetrics and Gynaecology Diseases, Hefei, Anhui, China
| | - Yongqi Fan
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Chao Zhang
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
- Anhui Provincial Institute of Translational Medicine, Hefei, Anhui, China
| | - Lei Sun
- Department of Clinical Medical, The First Clinical Medical College of Anhui Medical University, Hefei, Anhui, China
| | - Tingting Ye
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
| | - Qiushuang Wang
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
| | - Youhao Ban
- Hefei Anhua Trauma Rehabilitation Hospital, Hefei, Anhui, China
| | - Yunxia Cao
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
| | - Huijuan Zou
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China.
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China.
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei, Anhui, China.
| | - Zhiguo Zhang
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China.
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China.
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei, Anhui, China.
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Kim TS, Yoon JY, Kim CH, Choi EJ, Kim YH, Kim EJ. Dexmedetomidine and LPS co-treatment attenuates inflammatory response on WISH cells via inhibition of p38/NF-κB signaling pathway. J Dent Anesth Pain Med 2022; 22:277-287. [PMID: 35991362 PMCID: PMC9358267 DOI: 10.17245/jdapm.2022.22.4.277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/04/2022] [Revised: 07/13/2022] [Accepted: 07/16/2022] [Indexed: 11/16/2022] Open
Abstract
Background Inflammatory dental diseases that occur during pregnancy can cause preterm labor and/or intrauterine growth restriction. Therefore, proactive treatment of dental diseases is necessary during pregnancy. Dexmedetomidine (DEX) is a widely used sedative in the dental field, but research on the effect of DEX on pregnancy is currently insufficient. In this study, we investigated the effects of co-treatment with DEX and lipopolysaccharide (LPS) on inflammatory responses in human amnion-derived WISH cells. Methods Human amnion-derived WISH cells were treated with 0.001, 0.01, 0.1, and 1 µg/mL DEX with 1 µg/mL LPS for 24 h. Cytotoxicity of WISH cells was evaluated by 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. The protein expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), p38, and nuclear factor kappa B (NF-κB) was examined by western blot analysis. The mRNA expression of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α was analyzed by real-time quantitative polymerase chain reaction. Results Co-treatment with DEX and LPS showed no cytotoxicity in the WISH cells. The mRNA expression of IL-1β and TNF-α decreased after co-treatment with DEX and LPS. DEX and LPS co-treatment decreased the protein expression of COX-2, PGE2, phospho-p38, and phospho-NF-κB in WISH cells. Conclusion Co-treatment with DEX and LPS suppressed the expression of COX-2 and PGE2, as well as pro-inflammatory cytokines such as IL-1β and TNF-α in WISH cells. In addition, the anti-inflammatory effect of DEX and LPS co-treatment was mediated by the inhibition of p38/NF-κB activation.
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Affiliation(s)
- Tae-Sung Kim
- Department of Dental Anesthesia and Pain Medicine, School of Dentistry, Pusan National University, Dental Research Institute, Yangsan, Republic of Korea
| | - Ji-Young Yoon
- Department of Dental Anesthesia and Pain Medicine, School of Dentistry, Pusan National University, Dental Research Institute, Yangsan, Republic of Korea
| | - Cheul-Hong Kim
- Department of Dental Anesthesia and Pain Medicine, School of Dentistry, Pusan National University, Dental Research Institute, Yangsan, Republic of Korea
| | - Eun-Ji Choi
- Department of Dental Anesthesia and Pain Medicine, School of Dentistry, Pusan National University, Dental Research Institute, Yangsan, Republic of Korea
| | - Yeon Ha Kim
- Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea
| | - Eun-Jung Kim
- Department of Dental Anesthesia and Pain Medicine, School of Dentistry, Pusan National University, Dental Research Institute, Yangsan, Republic of Korea
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Leimert KB, Xu W, Princ MM, Chemtob S, Olson DM. Inflammatory Amplification: A Central Tenet of Uterine Transition for Labor. Front Cell Infect Microbiol 2021; 11:660983. [PMID: 34490133 PMCID: PMC8417473 DOI: 10.3389/fcimb.2021.660983] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/30/2021] [Accepted: 06/30/2021] [Indexed: 11/23/2022] Open
Abstract
In preparation for delivery, the uterus transitions from actively maintaining quiescence during pregnancy to an active parturient state. This transition occurs as a result of the accumulation of pro-inflammatory signals which are amplified by positive feedback interactions involving paracrine and autocrine signaling at the level of each intrauterine cell and tissue. The amplification events occur in parallel until they reach a certain threshold, ‘tipping the scale’ and contributing to processes of uterine activation and functional progesterone withdrawal. The described signaling interactions all occur upstream from the presentation of clinical labor symptoms. In this review, we will: 1) describe the different physiological processes involved in uterine transition for each intrauterine tissue; 2) compare and contrast the current models of labor initiation; 3) introduce innovative models for measuring paracrine inflammatory interactions; and 4) discuss the therapeutic value in identifying and targeting key players in this crucial event for preterm birth.
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Affiliation(s)
- Kelycia B Leimert
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada
| | - Wendy Xu
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada
| | - Magdalena M Princ
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada
| | - Sylvain Chemtob
- Department of Pediatrics, Ophthalmology and Pharmacology, CHU Sainte-Justine Research Center, Montreal, QC, Canada
| | - David M Olson
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada
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Moylan HEC, Nguyen-Ngo C, Lim R, Lappas M. The short-chain fatty acids butyrate and propionate protect against inflammation-induced activation of mediators involved in active labor: implications for preterm birth. Mol Hum Reprod 2021; 26:452-468. [PMID: 32236411 DOI: 10.1093/molehr/gaaa025] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/02/2020] [Revised: 03/01/2020] [Indexed: 12/12/2022] Open
Abstract
Spontaneous preterm birth is a global health issue affecting up to 20% of pregnancies and leaves a legacy of neurodevelopmental complications. Inflammation has been implicated in a significant proportion of preterm births, where pro-inflammatory insults trigger production of additional pro-inflammatory and pro-labor mediators. Thus, novel therapeutics that can target inflammation may be a novel avenue for preventing preterm birth and improving adverse fetal outcomes. Short-chain fatty acids (SCFAs), such as butyrate and propionate, are dietary metabolites produced by bacterial fermentation of fiber in the gut. SCFAs are known to possess anti-inflammatory properties and have been found to function through G-coupled-receptors and histone deacetylases. Therefore, this study aimed to investigate the effect of SCFAs on pro-inflammatory and pro-labor mediators in an in vitro model of preterm birth. Primary human cells isolated from myometrium and fetal membranes (decidua, amnion mesenchymal and amnion epithelial cells) were stimulated with the pro-inflammatory cytokines tumor necrosis factor alpha (TNF) or interleukin 1B (IL1B). The SCFAs butyrate and propionate suppressed inflammation-induced expression of pro-inflammatory cytokines and chemokines, adhesion molecules, the uterotonic prostaglandin PGF2alpha and enzymes involved in remodeling of myometrium and degradation of the fetal membranes. Notably, propionate and butyrate also suppressed inflammation-induced prostaglandin signaling and myometrial cell contraction. These effects appear to be mediated through suppression of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation. These results suggest that the SCFAs may be able to prevent myometrial contractions and rupture of membranes. Further in vivo studies are warranted to identify the efficacy of SCFAs as a novel anti-inflammatory therapeutic to prevent inflammation-induced spontaneous preterm birth.
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Affiliation(s)
- Hope Eveline Carter Moylan
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia
| | - Caitlyn Nguyen-Ngo
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia
| | - Ratana Lim
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.,Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Martha Lappas
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.,Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
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5
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Kalansuriya DM, Lim R, Lappas M. In vitro selenium supplementation suppresses key mediators involved in myometrial activation and rupture of fetal membranes. Metallomics 2021; 12:935-951. [PMID: 32373896 DOI: 10.1039/d0mt00063a] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022]
Abstract
Spontaneous preterm birth, which can affect up to 20% of all pregnancies, is the greatest contributor to perinatal morbidity and mortality. Infection is the leading pathological cause of spontaneous preterm birth. Infection activates the maternal immune system, resulting in the upregulation of pro-inflammatory and pro-labor mediators that activate myometrial contractions and rupture of fetal membranes. Anti-inflammatory agents therefore have the potential for the prevention of spontaneous preterm birth. Selenium, an essential micronutrient, has been shown to be a potent anti-inflammatory regulator. Notably, clinical and epidemiological studies have suggested a link between selenium and preterm birth. Thus, the aim of this study was to assess the effect of selenite (an inorganic form of selenium) on the expression of pro-inflammatory and pro-labor mediators in human gestational tissues. Human fetal membranes and myometrium were pre-incubated with or without selenite before incubation with the bacterial product lipopolysaccharide (LPS) to stimulate inflammation associated with preterm birth. Selenite blocked LPS-induced expression of pro-inflammatory cytokines and chemokines and enzymes involved in remodelling of myometrium and degradation of fetal membranes. Of note, selenite also suppressed myometrial activation induced by inflammation as evidenced by a decrease in LPS-induced prostaglandin signalling and myometrial cell contractility. These effects of selenite were mediated by the MAPK protein ERK as selenite blunted LPS induced activation of ERK. In conclusion, selenite suppresses key mediators involved in inflammation induced activation of mediators involved in active labor in human fetal membranes and myometrium. These findings support recent clinical studies demonstrating selenium supplementation is associated with decreased incidence of spontaneous preterm birth.
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Affiliation(s)
- Dineli Matheesha Kalansuriya
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Level 4/163 Studley Road, Heidelberg, 3084, Victoria, Australia.
| | - Ratana Lim
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Level 4/163 Studley Road, Heidelberg, 3084, Victoria, Australia. and Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Martha Lappas
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Level 4/163 Studley Road, Heidelberg, 3084, Victoria, Australia. and Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
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Rajagopal S, Yang C, DeMars KM, Poddar R, Candelario-Jalil E, Paul S. Regulation of post-ischemic inflammatory response: A novel function of the neuronal tyrosine phosphatase STEP. Brain Behav Immun 2021; 93:141-155. [PMID: 33422638 PMCID: PMC7979508 DOI: 10.1016/j.bbi.2020.12.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/27/2020] [Revised: 12/19/2020] [Accepted: 12/31/2020] [Indexed: 12/23/2022] Open
Abstract
The neuron-specific tyrosine phosphatase STEP is emerging as a key neuroprotectant against acute ischemic stroke. However, it remains unclear how STEP impacts the outcome of stroke. We find that the exacerbation of ischemic brain injury in STEP deficient mice involves an early onset and sustained activation of neuronal p38 mitogen activated protein kinase, a substrate of STEP. This leads to rapid increase in the expression of neuronal cyclooxygenase-2 and synthesis of prostaglandin E2, causing change in microglial morphology to an amoeboid activated state, activation of matrix metalloproteinase-9, cleavage of tight junction proteins and extravasation of IgG into the ischemic brain. Restoration of STEP signaling with intravenous administration of a STEP-derived peptide mimetic reduces the post-ischemic inflammatory response and attenuates brain injury. The findings identify a unique role of STEP in regulating post-ischemic neuroinflammation and further emphasizes the therapeutic potential of the STEP-mimetic in neurological disorders where inflammation contributes to brain damage.
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Affiliation(s)
| | - Changjun Yang
- University of Florida, Department of Neuroscience, USA
| | | | - Ranjana Poddar
- University of New Mexico Health Sciences Center, Department of Neurology, USA
| | | | - Surojit Paul
- University of New Mexico Health Sciences Center, Department of Neurology, USA; University of New Mexico Health Sciences Center, Department of Neuroscience, USA.
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7
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Abstract
The Cordyceps extract exhibits antiproliferative potential in vascular smooth muscle cells (SMCs) through the mitogen-activated protein kinase signaling pathway. In this study, we aimed to identify the active compounds in the Cordyceps extract and analyze their role in remodeling the arterial wall. On investigation, we discovered the following active compound: 4-methoxyphenyl (E)-3-(furan-3-yl) acrylate and synthesized it. We performed antiproliferation and antimigration assays in addition to an in vivo vessel wall remodeling experiment. Investigation of the mechanism adopted by the active compound to remodel the vessel was performed. The newly synthesized compound inhibited the proliferation and migration of SMCs. Treatment with the synthesized compound reduced neointima formation in the balloon-injured Sprague-Dawley rat model. In addition, this compound inhibited the activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 in type I collagen-activated SMCs. Moreover, this compound suppressed the expression of cycloxygenase-2 (COX-2) in SMCs. Therefore, this compound can exert potential antiarteriosclerotic effects by modulating vessel wall remodeling. In conclusion, the newly synthesized 4-methoxyphenyl (E)-3-(furan-3-yl) acrylate might be an alternative therapeutic intervention for the treatment of atherosclerosis.
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8
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Leimert KB, Verstraeten BSE, Messer A, Nemati R, Blackadar K, Fang X, Robertson SA, Chemtob S, Olson DM. Cooperative effects of sequential PGF2α and IL-1β on IL-6 and COX-2 expression in human myometrial cells†. Biol Reprod 2020; 100:1370-1385. [PMID: 30794283 DOI: 10.1093/biolre/ioz029] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/26/2018] [Revised: 10/17/2018] [Accepted: 02/20/2019] [Indexed: 12/15/2022] Open
Abstract
The change from the state of pregnancy to the state of parturition, which we call uterine transitioning, requires the actions of inflammatory mediators and results in an activated uterus capable of performing the physiology of labor. Interleukin (IL)-1β and prostaglandin (PG)F2α are two key mediators implicated in preparing the uterus for labor by regulating the expression of uterine activation proteins (UAPs) and proinflammatory cytokines and chemokines. To investigate this process, primary human myometrial smooth muscle cells (HMSMC) isolated from the lower segment of women undergoing elective cesarean sections at term (not in labor) were used to test the inflammatory cytokine and UAP outputs induced by PGF2α and IL-1β alone or in sequential combinations. PGF2α and IL-1β regulate mRNA abundance of the PGF2α receptor FP, the IL-1 receptor system, interleukin 6, and other UAPs (OXTR, COX2), driving positive feedback interactions to further amplify their own proinflammatory effects. Sequential stimulation of HMSMC by PGF2α and IL-1β in either order results in amplified upregulation of IL-6 and COX-2 mRNA and protein, compared to their effects individually. These profound increases were unique to myometrium and not observed with stimulation of human fetal membrane explants. These results suggest that PGF2α and IL-1β act cooperatively upstream in the birth cascade to maximize amplification of IL-6 and COX-2, to build inflammatory load and thereby promote uterine transition. Targeting PGF2α or IL-1β, their actions, or intermediates (e.g. IL-6) would be an effective therapeutic intervention for preterm birth prevention or delay.
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Affiliation(s)
- Kelycia B Leimert
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
| | | | - Angela Messer
- Department of Obstetrics, Gynecology and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Rojin Nemati
- Department of Obstetrics, Gynecology and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Kayla Blackadar
- Department of Obstetrics, Gynecology and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Xin Fang
- Department of Obstetrics, Gynecology and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Sarah A Robertson
- Department of Obstetrics and Gynecology, University of Adelaide, Adelaide, South Australia, Australia
| | - Sylvain Chemtob
- Department of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, Montréal, Quebec, Canada
| | - David M Olson
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.,Department of Obstetrics, Gynecology and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
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9
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Rostamtabar M, Esmaeilzadeh S, Tourani M, Rahmani A, Baee M, Shirafkan F, Saleki K, Mirzababayi SS, Ebrahimpour S, Nouri HR. Pathophysiological roles of chronic low-grade inflammation mediators in polycystic ovary syndrome. J Cell Physiol 2020; 236:824-838. [PMID: 32617971 DOI: 10.1002/jcp.29912] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/06/2020] [Revised: 05/28/2020] [Accepted: 06/15/2020] [Indexed: 12/29/2022]
Abstract
Polycystic ovary syndrome (PCOS) is the most common hormonal imbalance disease in reproductive-aged women. Its basic characteristics are ovulatory dysfunction and ovarian overproduction of androgens that lead to severe symptoms such as insulin resistance, hirsutism, infertility, and acne. Notwithstanding the disease burden, its underlying mechanisms remain unknown, and no causal therapeutic exists. In recent years, further studies showed that inflammation processes are involved in ovulation and play a key role in ovarian follicular dynamics. Visceral adipose tissue can cause inflammatory response and maintenance of the inflammation state in adipocytes by augmented production of inflammatory cytokines, monocyte chemoattractant proteins, and recruitment of the immune cell. Therefore, the PCOS can be related to a low-grade inflammation state and inflammatory markers. Investigating the inflammatory processes and mediators that contribute to the commencement and development of PCOS can be a critical step for better understanding the pathophysiology of the disease and its treatment through inhibition or control of related pathways. In the present review, we discuss the pathophysiological roles of chronic low-grade inflammation mediators including inflammasome-related cytokines, interleukin-1β (IL-1β), and IL-18 in PCOS development.
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Affiliation(s)
- Maryam Rostamtabar
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Sedigheh Esmaeilzadeh
- Infertility and Reproductive Health Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
| | - Mehdi Tourani
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Abolfazl Rahmani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Masoud Baee
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Fatemeh Shirafkan
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Kiarash Saleki
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | - Soheil Ebrahimpour
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Hamid Reza Nouri
- Infertility and Reproductive Health Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran.,Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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10
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Equils O, Kellogg C, McGregor J, Gravett M, Neal-Perry G, Gabay C. The role of the IL-1 system in pregnancy and the use of IL-1 system markers to identify women at risk for pregnancy complications†. Biol Reprod 2020; 103:684-694. [PMID: 32543660 DOI: 10.1093/biolre/ioaa102] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/16/2019] [Revised: 05/21/2020] [Accepted: 06/12/2020] [Indexed: 12/15/2022] Open
Abstract
The interleukin (IL)-1 system plays a major role in immune responses and inflammation. The IL-1 system components include IL-1α, IL-1β, IL-1 receptor type 1 and IL-1 receptor type 2 (decoy receptor), IL-1 receptor accessory protein, and IL-1 receptor antagonist (IL-1Ra). These components have been shown to play a role in pregnancy, specifically in embryo-maternal communication for implantation, placenta development, and protection against infections. As gestation advances, maternal tissues experience increasing fetal demand and physical stress and IL-1β is induced. Dependent on the levels of IL-1Ra, which regulates IL-1β activity, a pro-inflammatory response may or may not occur. If there is an inflammatory response, prostaglandins are synthesized that may lead to myometrial contractions and the initiation of labor. Many studies have examined the role of the IL-1 system in pregnancy by independently measuring plasma, cervical, and amniotic fluid IL-1β or IL-1Ra levels. Other studies have tested for polymorphisms in IL-1β and IL-1Ra genes in women experiencing pregnancy complications such as early pregnancy loss, in vitro fertilization failure, pre-eclampsia and preterm delivery. Data from those studies suggest a definite role for the IL-1 system in successful pregnancy outcomes. However, as anticipated, the results varied among different experimental models, ethnicities, and disease states. Here, we review the current literature and propose that measurement of IL-1Ra in relation to IL-1 may be useful in predicting the risk of poor pregnancy outcomes.
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Affiliation(s)
| | - Caitlyn Kellogg
- RPI Consulting LLC, Los Angeles, CA, USA.,San Diego School of Medicine, University of California, San Diego, CA, USA
| | | | - Michael Gravett
- Department of Obstetrics and Gynecology, University of Washington Medical Center, Seattle, WA, USA
| | - Genevieve Neal-Perry
- Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Cem Gabay
- University of Geneva, Geneva, Switzerland
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11
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Leimert KB, Messer A, Gray T, Fang X, Chemtob S, Olson DM. Maternal and fetal intrauterine tissue crosstalk promotes proinflammatory amplification and uterine transition†. Biol Reprod 2020; 100:783-797. [PMID: 30379983 DOI: 10.1093/biolre/ioy232] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/18/2018] [Revised: 10/06/2018] [Accepted: 10/29/2018] [Indexed: 12/24/2022] Open
Abstract
Birth is a complex biological event requiring genetic, cellular, and physiological changes to the uterus, resulting in a uterus activated for completing the physiological processes of labor. We define the change from the state of pregnancy to the state of parturition as uterine transitioning, which requires the actions of inflammatory mediators and localized paracrine interactions between intrauterine tissues. Few studies have examined the in vitro interactions between fetal and maternal gestational tissues within this proinflammatory environment. Thus, we designed a co-culture model to address this gap, incorporating primary term human myometrium smooth muscle cells (HMSMCs) with human fetal membrane (hFM) explants to study interactions between the tissues. We hypothesized that crosstalk between tissues at term promotes proinflammatory expression and uterine transitioning for parturition. Outputs of 40 cytokines and chemokines encompassing a variety of proinflammatory roles were measured; all but one increased significantly with co-culture. Eighteen of the 39 cytokines increased to a higher abundance than the sum of the effect of each tissue cultured separately. In addition, COX2 and IL6 but not FP and OXTR mRNA abundance significantly increased in both HMSMCs and hFM in response to co-culture. These data suggest that synergistic proinflammatory upregulation within intrauterine tissues is involved with uterine transitioning.
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Affiliation(s)
- Kelycia B Leimert
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
| | - Angela Messer
- Departments of Obstetrics & Gynecology, and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Theora Gray
- Departments of Obstetrics & Gynecology, and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Xin Fang
- Departments of Obstetrics & Gynecology, and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Sylvain Chemtob
- Department of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada
| | - David M Olson
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.,Departments of Obstetrics & Gynecology, and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
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Hantoushzadeh S, Anvari Aliabad R, Norooznezhad AH. Antibiotics, Inflammation, and Preterm Labor: A Missed Conclusion. J Inflamm Res 2020; 13:245-254. [PMID: 32547156 PMCID: PMC7261809 DOI: 10.2147/jir.s248382] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/04/2020] [Accepted: 04/14/2020] [Indexed: 12/30/2022] Open
Abstract
Regarding the risk of antibiotic therapy during pregnancy, any medication given to the mother should be according to the indications due to the risk of possible side effects. Antibiotics are one of the most important groups of these medications to be considered. Along with direct antibiotic-induced side effects, indirect pathways also affect the fetus through the maternal changes. According to the data, different cytokines including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) are involved in both term and preterm parturition. These cytokines could trigger expression of different substances such as prostaglandins (PGs), their receptors, and PGs synthetizing molecules with already proven roles in parturition. Moreover, IL-1, IL-6, and TNF-α knocked-out mice have delayed parturition and lower levels of PGs compared to the wild types. The earlier-mentioned cytokines are able to induce matrix metalloproteinases and are also involved in parturition. Certain antibiotics have been shown capable of inducing inflammation cascade directly. Both in-vivo and in-vitro studies in human have also demonstrated this inflammation as elevated levels of inflammatory cytokines especially IL-1, IL-6, and TNF-α. This increase has been observed both in the presence and the absence of lipopolysaccharide (LPS). Moreover, antibiotics can induce endotoxemia in healthy cases which finally leads to the pro-inflammatory cytokine release. Regarding the role of mentioned pro-inflammatory cytokines in both term and preterm parturition, it seems that non-indicated use of antibiotics during pregnancy may increase the risk of preterm labor.
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Affiliation(s)
- Sedigheh Hantoushzadeh
- Maternal, Fetal and Neonatal Research Center, Vali-Asr Hospital, Imam Khomeini Hospital Complexes, Tehran University of Medical Sciences, Tehran, Iran
| | - Roghayeh Anvari Aliabad
- Department of Gynecology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Amir Hossein Norooznezhad
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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13
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Rajagopal S, Fitzgerald AA, Deep SN, Paul S, Poddar R. Role of GluN2A NMDA receptor in homocysteine-induced prostaglandin E2 release from neurons. J Neurochem 2019; 150:44-55. [PMID: 31125437 DOI: 10.1111/jnc.14775] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/17/2019] [Revised: 05/07/2019] [Accepted: 05/21/2019] [Indexed: 12/22/2022]
Abstract
Hyperhomocysteinemia or systemic elevation of homocysteine is a metabolic condition that has been linked to multiple neurological disorders where inflammation plays an important role in the progression of the disease. However, it is unclear whether hyperhomocysteinemia contributes to disease pathology by inducing an inflammatory response. The current study investigates whether exposure of primary cultures from rat and mice cortical neurons to high levels of homocysteine induces the expression and release of the proinflammatory prostanoid, Prostaglandin E2 (PGE2). Using enzymatic assays and immunoblot analysis we show concurrent increase in the activity of cytosolic phospholipase A2 (cPLA2) and level of cyclooxygenase-2 (COX2), two enzymes involved in PGE2 biosynthesis. The findings also show an increase in PGE2 release from neurons. Pharmacological inhibition of GluN2A-containing NMDAR (GluN2A-NMDAR) with NVP-AAM077 significantly reduces homocysteine-induced cPLA2 activity, COX2 expression, and subsequent PGE2 release. Whereas, inhibition of GluN2B-containing NMDAR (GluN2A-NMDAR) with Ro 25-6981 has no effect. Complementary studies in neuron cultures obtained from wild type and GluN2A knockout mice show that genetic deletion of GluN2A subunit of NMDAR attenuates homocysteine-induced neuronal increase in cPLA2 activity, COX2 expression, and PGE2 release. Pharmacological studies further establish the role of both extracellular-regulated kinase/mitogen-activated protein kinase and p38 MAPK in homocysteine-GluN2A NMDAR-dependent activation of cPLA2-COX2-PGE2 pathway. Collectively, these findings reveal a novel role of GluN2A-NMDAR in facilitating homocysteine-induced proinflammatory response in neurons.
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Affiliation(s)
- Sathyanarayanan Rajagopal
- Department of Neurology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico, USA
| | - Ashley Anne Fitzgerald
- Department of Neurology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico, USA
| | - Satya Narayan Deep
- Department of Neurology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico, USA
| | - Surojit Paul
- Department of Neurology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico, USA
| | - Ranjana Poddar
- Department of Neurology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico, USA
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Lim R, Barker G, Lappas M. PARK7 regulates inflammation-induced pro-labour mediators in myometrial and amnion cells. Reproduction 2018; 155:207-218. [PMID: 29358306 DOI: 10.1530/rep-17-0604] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/05/2017] [Revised: 11/13/2017] [Accepted: 12/04/2017] [Indexed: 01/18/2023]
Abstract
Preterm birth is a prevalent cause of neonatal deaths worldwide. Inflammation has been implicated in spontaneous preterm birth involved in the processes of uterine contractility and membrane rupture. Parkinson protein 7 (PARK7) has been found to play an inflammatory role in non-gestational tissues. The aims of this study were to determine the expression of PARK7 in myometrium and fetal membranes with respect to term labour onset and to elucidate the effect of PARK7 silencing in primary myometrium and amnion cells on pro-inflammatory and pro-labour mediators. PARK7 mRNA expression was higher in term myometrium and fetal membranes from women in labour compared to non-labouring samples and in amnion from preterm deliveries with chorioamnionitis. In human primary myometrial cells transfected with PARK7 siRNA (siPARK7), there was a significant decrease in IL1B, TNF, fsl-1 and poly(I:C)-induced expression of pro-inflammatory cytokine IL6, chemokines (CXCL8, CCL2), adhesion molecule ICAM1, prostaglandin PGF2α and its receptor PTGFR. Similarly, amnion cells transfected with siPARK7 displayed a decrease in IL1B-induced expression of IL6, CXCL8 and ICAM1. In myometrial cells transfected with siPARK7, there was a significant reduction of NF-κB RELA transcriptional activity when stimulated with fsl-1, flagellin and poly(I:C), but not with IL1B or TNF. Collectively, our novel data describe a role for PARK7 in regulating inflammation-induced pro-inflammatory and pro-labour mediators in human myometrial and amnion cells.
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Affiliation(s)
- Ratana Lim
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of MelbourneMelbourne, Victoria, Australia.,Mercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Gillian Barker
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of MelbourneMelbourne, Victoria, Australia.,Mercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Martha Lappas
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of MelbourneMelbourne, Victoria, Australia .,Mercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, Australia
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15
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Wijesuriya YK, Lappas M. Potent anti-inflammatory effects of honokiol in human fetal membranes and myometrium. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2018; 49:11-22. [PMID: 30217257 DOI: 10.1016/j.phymed.2018.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 12/30/2017] [Revised: 03/13/2018] [Accepted: 06/06/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND Preterm birth is the most prominent complication attributing to poor pregnancy and neonatal outcome. Infection is most commonly implicated in preterm birth; it initiates a cascade of inflammatory events that leads to the rupture of fetal membranes and spontaneous uterine contractions. Anti-inflammatory agents may thus be a therapeutic approach to prevent the premature rupture of fetal membranes and block contractions. In non-gestational tissues, the polyphenol honokiol has been shown to possess potent anti-inflammatory properties. PURPOSE The aim of this study was to investigate the effect of honokiol on pro-inflammatory mediators in human gestational tissues. METHODS Fetal membranes, myometrium and freshly isolated amnion cells and primary myometrial cells were treated with honokiol in the absence or presence of the products lipopolysaccharide (LPS) and fibroblast-stimulating lipopeptide-1 (fsl-1), the viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) or the pro-inflammatory cytokines TNF or IL1B. A luciferase assay was used to determine the effect of honokiol on nuclear factor kappa B (NF-κB) RelA transcriptional activity. RESULTS Honokiol significantly decreased pro-inflammatory cytokine (IL1A, IL6) and chemokine (CXCL8, CXCL1, CCL2) mRNA expression and secretion from fetal membranes (amnion and choriodecidua) and myometrium stimulated with LPS, fsl-1 or poly(I:C). In amnion cells, honokiol also significantly decreased the expression and secretion of the extracellular matrix degrading enzyme MMP9. Moreover, in myometrium, honokiol significantly suppressed the expression of the contraction associated protein PTGFR, the secretion of the uterotonic prostaglandins PGE2 and PGF2α, and blocked TNF-induced myometrial cell contractility. Finally, honokiol significantly suppressed IL1B- and TNF-induced NF-κB RelA transcriptional activity in primary amnion and myometrial cells. CONCLUSIONS Honokiol reduced the expression of pro-inflammatory and pro-labour mediators in human amnion, choriodecidua and myometrium and that this may be facilitated through the suppression of NF-κB activation. These results indicate that the polyphenol honokiol may be a potent therapeutic for the prevention of preterm birth.
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Affiliation(s)
- Yasaswi Kaumadha Wijesuriya
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia
| | - Martha Lappas
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
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DREAM Is Involved in the Genesis of Inflammation-Induced Prolabour Mediators in Human Myometrial and Amnion Cells. BIOMED RESEARCH INTERNATIONAL 2018; 2018:8237087. [PMID: 29682558 PMCID: PMC5842746 DOI: 10.1155/2018/8237087] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 11/07/2017] [Accepted: 01/17/2018] [Indexed: 01/31/2023]
Abstract
Preterm birth is the primary cause of perinatal morbidity and mortality worldwide. Inflammation induces a cascade of events leading to preterm birth by activating nuclear factor-κB (NF-κB). In nongestational tissues, downstream regulatory element antagonist modulator (DREAM) regulates NF-κB activity. Our aims were to analyse DREAM expression in myometrium and fetal membranes obtained at term and preterm and to determine the effect of DREAM inhibition on prolabour mediators in primary myometrial and amnion cells. DREAM mRNA expression was significantly higher in fetal membranes obtained after spontaneous labour compared to nonlabour and in amnion from women with histological preterm chorioamnionitis when compared to amnion from women without chorioamnionitis. In primary myometrial and amnion cells, the effect of DREAM silencing by siRNA was a significant decrease in the expression of proinflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, the adhesion molecule ICAM-1, MMP-9 mRNA expression and activity, and NF-κB transcriptional activity when stimulated with the proinflammatory cytokine IL-1β, the bacterial products fsl-1 or flagellin, or the viral dsRNA analogue poly(I:C). These data suggest that, in states of heightened inflammation, DREAM mRNA expression is increased and that, in myometrial and amnion cells, DREAM regulates proinflammatory and prolabour mediators which may be mediated via NF-κB.
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17
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Lappas M. RKIP is decreased in laboring myometrium and modulates inflammation-induced pro-labor mediators. Reproduction 2017; 153:545-553. [PMID: 28280133 DOI: 10.1530/rep-17-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/04/2017] [Revised: 02/06/2017] [Accepted: 02/13/2017] [Indexed: 11/08/2022]
Abstract
Nuclear factor-kappa B (NF-κB)-induced inflammation plays a central role in the terminal process of human labor and delivery. Our previous studies show that IL1B induces NF-κB signaling through extracellular signal-regulated kinase (ERK; official gene symbol MAPK1), whereas TNF induces NF-κB-driven transcription of pro-labor mediators via an MAPK1-independent mechanism. Raf kinase inhibitor protein (RKIP) negatively regulates inflammation by inhibiting NF-κB activation directly or indirectly by inhibiting MAPK1. The role of RKIP in the processes of human labor and delivery is not known. The present study was performed to investigate the expression of RKIP in laboring and non-laboring human myometrium and determine the effect of siRNA knockdown of RKIP (siRKIP) on pro-labor mediators in human myometrial primary cells. Term labor was associated with a decrease in RKIP expression. Furthermore, RKIP expression was decreased in myometrial cells treated with IL1B and TNF, two likely factors contributing to preterm birth. The effect of siRKIP in primary myometrial cells was a significant augmentation of IL1B- and TNF-induced CXCL1 and CXCL8 mRNA abundance and secretion; PTGS2 mRNA levels and prostaglandin PGF2α release and MMP9 mRNA abundance and pro-MMP9 secretion. There was no effect of siRKIP on MAPK1 activation. On the other hand, RKIP knockdown was associated with increased activation of NF-κB RELA in the presence of IL1B and TNF. In conclusion, in human primary myometrial cells, RKIP negatively regulates IL1B- and TNF-induced expression and or secretion of pro-inflammatory and pro-labor mediators by inhibiting NF-κB RELA activation.
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Affiliation(s)
- Martha Lappas
- Mercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, Australia and Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne,Victoria, Australia
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18
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Sivarajasingam SP, Imami N, Johnson MR. Myometrial cytokines and their role in the onset of labour. J Endocrinol 2016; 231:R101-R119. [PMID: 27647860 DOI: 10.1530/joe-16-0157] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/02/2016] [Accepted: 09/19/2016] [Indexed: 12/12/2022]
Abstract
Human labour is an inflammatory event, physiologically driven by an interaction between hormonal and mechanical factors and pathologically associated with infection, bleeding and excessive uterine stretch. The initiation and communicators of inflammation is still not completely understood; however, a key role for cytokines has been implicated. We summarise the current understanding of the nature and role of cytokines, chemokines and hormones and their involvement in signalling within the myometrium particularly during labour.
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Affiliation(s)
- S P Sivarajasingam
- Department of Surgery and CancerImperial College London, Chelsea and Westminster Hospital, London, UK
| | - N Imami
- Department of MedicineImperial College London, London, UK
| | - M R Johnson
- Department of Surgery and CancerImperial College London, Chelsea and Westminster Hospital, London, UK
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19
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Zhu Y, Tan YQ, Leung LK. Aflatoxin B1 disrupts transient receptor potential channel activity and increases COX-2 expression in JEG-3 placental cells. Chem Biol Interact 2016; 260:84-90. [PMID: 27818125 DOI: 10.1016/j.cbi.2016.11.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/09/2016] [Revised: 10/05/2016] [Accepted: 11/01/2016] [Indexed: 02/06/2023]
Abstract
Aflatoxins are fungal metabolites which pose a major threat to food safety. Although these mycotoxins are established hepatocarcinogens, their effect on the reproductive organ is unknown. Transient Receptor Potential Channels (TRPs) are ubiquitously expressed in human tissues, including the placenta. These channels are associated with various functions in the placenta. The fetus and the placenta are especially sensitive to xenobiotic assault; therefore, exposure to the aflatoxins during gestation might lead to the undesirable outcome. Previously we have shown that aflatoxin B1 administered in late gestation may increase cox-2 expression in mouse placentae. In the present study, we examined the effect of aflatoxin B1 on COX-2 by using the placental cell model JEG-3 and the respective signaling pathway. In our result, COX-2 expression was induced by the mycotoxin administration. The intracellular calcium levels were also increased in cells by aflatoxin B1 treatment as little as 1 nM. Immunoblot result showed that some TRP expressions were elevated. As inflated intracellular calcium might activate MAPKs, the underlying signaling pathway was investigated. With the help of TRP-specific inhibitors, the mycotoxin appeared to increase the expression of TRPC-3 and activate PKCβ and ERK. The significance of COX-2 in pregnancy has been well established. Exposure to this mycotoxin may perturb the physiological processes dictated by COX-2 in pregnancy.
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Affiliation(s)
- Yun Zhu
- Food and Nutritional Sciences Programme, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Yan Qin Tan
- Food and Nutritional Sciences Programme, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Lai K Leung
- Food and Nutritional Sciences Programme, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong; Biochemistry Programme, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
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20
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Ishiguro T, Takeda J, Fang X, Bronson H, Olson DM. Interleukin (IL)-1 in rat parturition: IL-1 receptors 1 and 2 and accessory proteins abundance in pregnant rat uterus at term - regulation by progesterone. Physiol Rep 2016; 4:4/14/e12866. [PMID: 27440742 PMCID: PMC4962072 DOI: 10.14814/phy2.12866] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/27/2016] [Accepted: 06/13/2016] [Indexed: 11/24/2022] Open
Abstract
The role of interleukin-1 (IL-1), a pro-inflammatory cytokine, in parturition is typically noted by changes in its concentrations. Studying the expression of its receptor family, IL-1 receptor (IL-1R) 1, IL-1R2, IL-1R accessory protein (IL-1RAcP), and its predominantly brain isoform, IL-1RAcPb, during late gestation in the uterus in the Long-Evans rat is another. We assessed changes in their mRNA and protein relative abundance in the uterus and compared IL-1RAcP and IL-1RAcPb mRNA abundance in uterus, cervix, ovaries, placenta, and whole blood of Long-Evans rats during late gestation or in RU486 and progesterone-treated dams using quantitative real-time PCR and western immunoblotting. IL-1R1, IL-1RAcP, and IL-1RAcPb mRNA abundance significantly increased in the uterus at delivery whereas IL-1R2 mRNA abundance significantly decreased. IL-1R1 protein increased at term and IL-1R2 protein decreased at term compared to nonpregnant uteri. IL1-RAcPb mRNA abundance was less than IL-1RAcP, but in the lower uterine segment it was the highest of all tissues examined. RU486 stimulated preterm delivery and an increase in IL-1R1 mRNA abundance whereas progesterone administration extended pregnancy and suppressed the increase in IL-1R1. These data suggest that changes in uterine sensitivity to IL-1 occur during late gestation and suggest another level of regulation for the control of delivery. The roles for IL-1RAcP and IL-1RAcPb need to be determined, but may relate to different intracellular signaling pathways.
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Affiliation(s)
- Tomohito Ishiguro
- Departments of Obstetrics and Gynecology, Physiology & Pediatrics, University of Alberta, Edmonton, Canada Departments of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan Departments of Obstetrics and Gynecology, Koshigaya Municipal Hospital, Koshigaya, Japan
| | - Jun Takeda
- Departments of Obstetrics and Gynecology, Physiology & Pediatrics, University of Alberta, Edmonton, Canada Departments of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Xin Fang
- Departments of Obstetrics and Gynecology, Physiology & Pediatrics, University of Alberta, Edmonton, Canada
| | - Heather Bronson
- Departments of Obstetrics and Gynecology, Physiology & Pediatrics, University of Alberta, Edmonton, Canada
| | - David M Olson
- Departments of Obstetrics and Gynecology, Physiology & Pediatrics, University of Alberta, Edmonton, Canada
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21
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Lappas M. The Adaptor Protein p62 Mediates Nuclear Factor κB Activation in Response to Inflammation and Facilitates the Formation of Prolabor Mediators in Human Myometrium. Reprod Sci 2016; 24:762-772. [PMID: 27638291 DOI: 10.1177/1933719116669058] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/23/2022]
Abstract
Preventing spontaneous preterm birth is one of the most important issues facing perinatal medicine today. The pathophysiology of preterm labor, the single biggest cause of preterm birth, is poorly understood. Inflammation, however, plays a significant role in the terminal processes of human labor, which include myometrial contractions. Nuclear factor κB (NF-κB) drives the transcription of proinflammatory mediators involved in the terminal effector pathways of human labor and delivery. Recent studies in nongestational tissues have shown that the adaptor protein p62 interacts with NF-κB to induce inflammation. The aim of this study was to determine the role of p62 in the genesis of NF-κB-induced proinflammatory and prolabur mediators. Human spontaneous term labor was associated with increased p62 messenger RNA (mRNA) and protein expression in myometrium. Myometrial cells treated with proinflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) also significantly increased p62 mRNA and protein expression. Functional studies using p62 small interfering RNA (siRNA) demonstrated a significant attenuation of TNF-α- and IL-1β-induced proinflammatory cytokines (IL-6) and chemokine (IL-8 and monocyte chemoattractant protein 1 [MCP-1]) mRNA expression and secretion, expression of cyclooxygenase 2, release of prostaglandin F2α (PGF2α), and expression of the prostaglandin F receptor (FP). In addition, siRNA knockdown of p62 significantly suppressed IL-1β- and TNF-α-induced NF-κB activation. Collectively, these studies suggest that p62 is involved in the genesis of NF-κB-induced proinflammatory and prolabor mediators.
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Affiliation(s)
- Martha Lappas
- 1 Department of Obstetrics and Gynaecology, University of Melbourne, Obstetrics, Nutrition and Endocrinology Group, Victoria, Australia.,2 Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
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22
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Lim R, Barker G, Menon R, Lappas M. A Novel Role for SIRT3 in Regulating Mediators Involved in the Terminal Pathways of Human Labor and Delivery. Biol Reprod 2016; 95:95. [PMID: 27628218 PMCID: PMC5333934 DOI: 10.1095/biolreprod.116.142372] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/01/2016] [Accepted: 09/06/2016] [Indexed: 12/24/2022] Open
Abstract
Preterm birth remains the major cause of neonatal mortality and morbidity, mediated largely by an inflammatory process. The sirtuin (SIRT) family of cellular regulators has been implicated as key inhibitors of inflammation. We have previously reported a role for SIRT1, SIRT2, and SIRT6 in regulating inflammation-induced prolabor mediators. In this study, we determined the effect of term labor and pro-inflammatory cytokines on SIRT3, SIRT4, SIRT5, and SIRT7 expression in human myometrium. Functional studies were also used to investigate the effect of small interfering RNA (siRNA) knockdown of SIRTs in regulating inflammation-induced prolabor mediators. Western blot analysis and qRT-PCR were used to determine SIRT3, SIRT4, SIRT5, and SIRT7 mRNA and protein expression in human myometrium. Small interfering RNA knockdown of SIRT3 in myometrial primary cells determined its role in response to inflammatory stimuli IL1B and TNF. SIRT3 mRNA and protein expression levels were significantly lower in term laboring myometrium compared with term nonlaboring myometrium. There was no effect of labor on SIRT4, SIRT5 or SIRT7 protein expression. The pro-inflammatory cytokines IL1B and TNF significantly decreased levels of SIRT3 mRNA and protein expression. SIRT3 knockdown by siRNA significantly augmented IL1B- and TNF-stimulated IL6, CXCL8, and CCL2 mRNA expression and release; PTGS2 mRNA expression and subsequent PGF2alpha release; the mRNA expression and secretion of the adhesion molecule ICAM1 and the extracellular matrix remodeling enzyme MMP9; and nuclear factor kappa B1 (NFkappaB1) transcriptional activity. In human myometrium, SIRT3 expression decreases with term labor and regulates the mediators involved in the terminal effector pathways of human labor and delivery through the NFkappaB1 pathway.
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Affiliation(s)
- Ratana Lim
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.,Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Gillian Barker
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.,Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Ramkumar Menon
- Department of Obstetrics and Gynecology, Division of Perinatal Research, The University of Texas Medical Branch at Galveston, Galveston, Texas.,Department of Clinical Medicine and Obstetrics and Gynecology, Aarhus University, Aarhus, Denmark
| | - Martha Lappas
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia .,Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
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Guerrero CA, Acosta O. Inflammatory and oxidative stress in rotavirus infection. World J Virol 2016; 5:38-62. [PMID: 27175349 PMCID: PMC4861870 DOI: 10.5501/wjv.v5.i2.38] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/12/2015] [Revised: 10/23/2015] [Accepted: 01/29/2016] [Indexed: 02/05/2023] Open
Abstract
Rotaviruses are the single leading cause of life-threatening diarrhea affecting children under 5 years of age. Rotavirus entry into the host cell seems to occur by sequential interactions between virion proteins and various cell surface molecules. The entry mechanisms seem to involve the contribution of cellular molecules having binding, chaperoning and oxido-reducing activities. It appears to be that the receptor usage and tropism of rotaviruses is determined by the species, cell line and rotavirus strain. Rotaviruses have evolved functions which can antagonize the host innate immune response, whereas are able to induce endoplasmic reticulum (ER) stress, oxidative stress and inflammatory signaling. A networking between ER stress, inflammation and oxidative stress is suggested, in which release of calcium from the ER increases the generation of mitochondrial reactive oxygen species (ROS) leading to toxic accumulation of ROS within ER and mitochondria. Sustained ER stress potentially stimulates inflammatory response through unfolded protein response pathways. However, the detailed characterization of the molecular mechanisms underpinning these rotavirus-induced stressful conditions is still lacking. The signaling events triggered by host recognition of virus-associated molecular patterns offers an opportunity for the development of novel therapeutic strategies aimed at interfering with rotavirus infection. The use of N-acetylcysteine, non-steroidal anti-inflammatory drugs and PPARγ agonists to inhibit rotavirus infection opens a new way for treating the rotavirus-induced diarrhea and complementing vaccines.
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Lappas M. RAF1 is increased in labouring myometrium and modulates inflammation-induced pro-labour mediators. Reproduction 2016; 151:411-20. [DOI: 10.1530/rep-15-0607] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/21/2015] [Accepted: 01/25/2016] [Indexed: 01/25/2023]
Abstract
Inflammation plays a central role in the terminal process of human labour and delivery, including myometrial contractions. RAF1 proto-oncogene serine/threonine-protein kinase (RAF1) can activate ERK (official gene symbolMAPK1) and/or nuclear factor-kappa B (NF-κB) to regulate genes involved in inflammation. There are, however, no studies on the role of RAF1 in the processes of human labour and delivery. Thus, the aims of this study were to determine the effect of i) human labour and pro-inflammatory cytokines interleukin 1 beta (IL1B) and tumour necrosis factor (TNF) alpha on RAF1 protein expression in myometrium and ii) siRNA knockdown ofRAF1on pro-inflammatory and pro-labour mediators in human myometrial primary cells. Term labour was associated with an increase in RAF1 protein expression. Furthermore, RAF1 protein expression was increased in myometrial cells treated with IL1B and TNF, two likely factors contributing to preterm birth. Knockdown ofRAF1by siRNA in primary myometrial cells significantly decreased IL1B- and TNF-inducedIL1A, IL1B, IL6,(C-X-C motif) ligand 8 (CXCL8)and chemokine (C-C motif) ligand 2 (CCL2) mRNA abundance and IL6, IL8 and CCL2; prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA levels and prostaglandin PGF2αrelease; and NF-κB activation. Furthermore,RAF1knockdown was associated with decreased activation of ERK in the presence of IL1B but not TNF. Concordantly, the ERK inhibitor U0126 significantly decreased IL1B-inducedIL6,CXCL8,CCL2andPTGS2mRNA abundance; IL6, CXCL8, CCL2 and PGF2αrelease; and NF-κB activation. In conclusion, IL1B induces the expression and secretion of pro-labour mediators through the RAF1–MAPK1–NF-κB signalling pathway. TNF, on the other hand, regulates pro-labour mediators through the RAF1–NF-κB signalling pathway via an MAPK1-independent mechanism.
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Nadeau-Vallée M, Obari D, Quiniou C, Lubell WD, Olson DM, Girard S, Chemtob S. A critical role of interleukin-1 in preterm labor. Cytokine Growth Factor Rev 2015; 28:37-51. [PMID: 26684042 DOI: 10.1016/j.cytogfr.2015.11.001] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/21/2015] [Revised: 10/24/2015] [Accepted: 11/03/2015] [Indexed: 12/16/2022]
Abstract
Preterm birth (PTB) is a leading cause of neonatal mortality and morbidity worldwide, and represents a heavy economic and social burden. Despite its broad etiology, PTB has been firmly linked to inflammatory processes. Pro-inflammatory cytokines are produced in gestational tissues in response to stressors and can prematurely induce uterine activation, which precedes the onset of preterm labor. Of all cytokines implicated, interleukin (IL)-1 has been largely studied, revealing a central role in preterm labor. However, currently approved IL-1-targeting therapies have failed to show expected efficacy in pre-clinical studies of preterm labor. Herein, we (a) summarize animal and human studies in which IL-1 or IL-1-targeting therapeutics are implicated with preterm labor, (b) focus on novel IL-1-targeting therapies and diagnostic tests, and (c) develop the case for commercialization and translation means to hasten their development.
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Affiliation(s)
- Mathieu Nadeau-Vallée
- Departments of Pediatrics, Ophthalmology and Pharmacology, CHU Sainte-Justine Research Center, Montréal H3T 1C5, Canada; Department of Pharmacology, Université de Montréal, Montréal H3C 3J7, Canada
| | - Dima Obari
- Department of Pharmacology, Université de Montréal, Montréal H3C 3J7, Canada
| | - Christiane Quiniou
- Departments of Pediatrics, Ophthalmology and Pharmacology, CHU Sainte-Justine Research Center, Montréal H3T 1C5, Canada
| | - William D Lubell
- Department of Chemistry, Université de Montréal, Montréal, Québec H3C 3J7, Canada
| | - David M Olson
- Departments of Obstetrics and Gynecology, Pediatrics and Physiology, University of Alberta, Edmonton AB TG6 2S2, Canada
| | - Sylvie Girard
- Departments of Obstetrics and Gynecology, CHU Sainte-Justine Research Centre, Montréal H3T 1C5, Canada.
| | - Sylvain Chemtob
- Departments of Pediatrics, Ophthalmology and Pharmacology, CHU Sainte-Justine Research Center, Montréal H3T 1C5, Canada.
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Novembri R, De Clemente C, Funghi L, Torricelli M, Voltolini C, Challis JR, Petraglia F. Corticotropin releasing hormone and Urocortin 2 activate inflammatory pathways in cultured trophoblast cell lines. Eur J Obstet Gynecol Reprod Biol 2015; 195:200-205. [PMID: 26588439 DOI: 10.1016/j.ejogrb.2015.10.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/17/2015] [Revised: 06/26/2015] [Accepted: 10/28/2015] [Indexed: 01/04/2023]
Abstract
OBJECTIVE Embryo implantation and parturition are recognized as inflammatory events involving endocrine and immune system. NF-kB and MAPK are two transcription factor families involved in inflammation. A possible role of neuroendocrine mechanism in early pregnancy and delivery was proposed for the neuropeptides related to corticotropin releasing hormones (CRH), named Urocortins (Ucns). Experimental and clinical studies support a role for CRH, Ucn, Ucn2 and Ucn3 in the endocrine/immune modulation of inflammation in human trophoblast; however the intracellular mechanisms are not yet recognized. The aim of the present study was to evaluate which of these neuropeptides modulate NF-kB or MAPKs pathways. STUDY DESIGN In Jeg-3 placental cell line the effect of CRH, Ucn, Ucn2 or Ucn3 on NF-kB and MAPKs pathways were evaluated using Western blot analysis. RESULTS CRH induced the phosphorylation of MAPK subunits; Ucn2 was able to induce the phosphorylation of both NF-kB and MAPK subunits. Ucn and Ucn3 had no effects on these pathways. CONCLUSIONS These data provide novel information on inflammatory process in trophoblast cells: Ucn2 is a potent pro-inflammatory neuropeptide via NF-kB and MAPK pathways and CRH via MAPK, and CRH and Ucn2 network participates in the inflammatory mechanisms of pregnancy and parturition.
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Affiliation(s)
- Romina Novembri
- Department of Molecular and Developmental Medicine, University of Siena Viale Bracci, Siena, Italy
| | - Caterina De Clemente
- Department of Biotechnology, University of Siena, via Fiorentina 1, 53100 Siena, Italy
| | - Lucia Funghi
- Department of Molecular and Developmental Medicine, University of Siena Viale Bracci, Siena, Italy
| | - Michela Torricelli
- Department of Molecular and Developmental Medicine, University of Siena Viale Bracci, Siena, Italy
| | - Chiara Voltolini
- Department of Molecular and Developmental Medicine, University of Siena Viale Bracci, Siena, Italy
| | - John R Challis
- The University of Western Australia M460A, 35 Stirling Highway, Crawley, WA 6009, Australia
| | - Felice Petraglia
- Department of Molecular and Developmental Medicine, University of Siena Viale Bracci, Siena, Italy.
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Willets JM, Brighton PJ, Windell LN, Rana S, Nash CA, Konje JC. Bradykinin-activated contractile signalling pathways in human myometrial cells are differentially regulated by arrestin proteins. Mol Cell Endocrinol 2015; 407:57-66. [PMID: 25766502 DOI: 10.1016/j.mce.2015.03.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/05/2014] [Revised: 03/04/2015] [Accepted: 03/04/2015] [Indexed: 11/29/2022]
Abstract
Bradykinin is associated with infections and inflammation, which given the strong correlation between uterine infection and preterm labour may imply that it could play a role in this process. Therefore, we investigated bradykinin signalling, and the roles that arrestin proteins play in their regulation in human myometrial cells. Bradykinin induced rapid, transient intracellular Ca(2+) increases that were inhibited following B2 receptor (B2R) antagonism. Arrestin2 or arrestin3 depletion enhanced and prolonged bradykinin-stimulated Ca(2+) responses, and attenuated B2R desensitisation. Knockdown of either arrestin enhanced B2R-stimulated ERK1/2 signals. Moreover, depletion of either arrestin elevated peak-phase p38-MAPK signalling, yet only arrestin3 depletion prolonged B2R-induced p38-MAPK signals. Arrestin2-knockdown augmented bradykinin-induced cell movement. Bradykinin stimulates pro-contractile signalling mechanisms in human myometrial cells and arrestin proteins play key roles in their regulation. Our data suggest bradykinin not only acts as an utertonin, but may also have the potential to enhance the contractile environment of the uterus.
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Affiliation(s)
- J M Willets
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom.
| | - P J Brighton
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom
| | - L N Windell
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom
| | - S Rana
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom
| | - C A Nash
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom
| | - J C Konje
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom
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Xu C, You X, Liu W, Sun Q, Ding X, Huang Y, Ni X. Prostaglandin F2α regulates the expression of uterine activation proteins via multiple signalling pathways. Reproduction 2015; 149:139-146. [PMID: 25342173 DOI: 10.1530/rep-14-0479] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/21/2025]
Abstract
Prostaglandin F2α (PGF2A) has multiple roles in the birth process in addition to its vital contractile role. Our previous study has demonstrated that PGF2A can modulate uterine activation proteins (UAPs) in cultured pregnant human myometrial smooth muscle cells (HMSMCs). The objective of this study was to define the signalling pathways responsible for PGF2A modulation of UAPs in myometrium. It was found that PGF2A stimulated the expression of (GJA1) connexin 43 (CX43), prostaglandin endoperoxide synthase 2 (PTGS2) and oxytocin receptor (OTR) in cultured HMSMCs. The inhibitors of phospholipase C (PLC) and protein kinase C (PKC) blocked PGF2A-stimulated expression of CX43. The inhibitors of ERK, P38 and NFκB also blocked the effect of PGF2A on CX43 expression, whereas PI3K and calcineurin/nuclear factor of activated T-cells (NFAT) pathway inhibitors did not reverse the effect of PGF2A on CX43. For PTGS2 and OTR, PLC, PI3K, P38 and calcineurin/NFAT signalling pathways were involved in PGF2A action, whereas PKC and NFκB signalling were not involved. In addition, PGF2A activated NFAT, PI3K, NFκB, ERK and P38 signalling pathways. Our data suggest that PGF2A stimulates CX43, PTGS2 and OTR through divergent signalling pathways.
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Affiliation(s)
- Chen Xu
- Department of PhysiologySecond Military Medical University, 800 Xiangyin Road, Shanghai 200433, ChinaDepartment of Obstetrics and GynecologyChanghai Hospital, Shanghai, ChinaMaternity and Child Health Hospital of Pudong New District599 Hongfeng Road, Shanghai 201206, China
| | - Xingji You
- Department of PhysiologySecond Military Medical University, 800 Xiangyin Road, Shanghai 200433, ChinaDepartment of Obstetrics and GynecologyChanghai Hospital, Shanghai, ChinaMaternity and Child Health Hospital of Pudong New District599 Hongfeng Road, Shanghai 201206, China
| | - Weina Liu
- Department of PhysiologySecond Military Medical University, 800 Xiangyin Road, Shanghai 200433, ChinaDepartment of Obstetrics and GynecologyChanghai Hospital, Shanghai, ChinaMaternity and Child Health Hospital of Pudong New District599 Hongfeng Road, Shanghai 201206, China
| | - Qianqian Sun
- Department of PhysiologySecond Military Medical University, 800 Xiangyin Road, Shanghai 200433, ChinaDepartment of Obstetrics and GynecologyChanghai Hospital, Shanghai, ChinaMaternity and Child Health Hospital of Pudong New District599 Hongfeng Road, Shanghai 201206, China
| | - Xiaoying Ding
- Department of PhysiologySecond Military Medical University, 800 Xiangyin Road, Shanghai 200433, ChinaDepartment of Obstetrics and GynecologyChanghai Hospital, Shanghai, ChinaMaternity and Child Health Hospital of Pudong New District599 Hongfeng Road, Shanghai 201206, China Department of PhysiologySecond Military Medical University, 800 Xiangyin Road, Shanghai 200433, ChinaDepartment of Obstetrics and GynecologyChanghai Hospital, Shanghai, ChinaMaternity and Child Health Hospital of Pudong New District599 Hongfeng Road, Shanghai 201206, China
| | - Ying Huang
- Department of PhysiologySecond Military Medical University, 800 Xiangyin Road, Shanghai 200433, ChinaDepartment of Obstetrics and GynecologyChanghai Hospital, Shanghai, ChinaMaternity and Child Health Hospital of Pudong New District599 Hongfeng Road, Shanghai 201206, China
| | - Xin Ni
- Department of PhysiologySecond Military Medical University, 800 Xiangyin Road, Shanghai 200433, ChinaDepartment of Obstetrics and GynecologyChanghai Hospital, Shanghai, ChinaMaternity and Child Health Hospital of Pudong New District599 Hongfeng Road, Shanghai 201206, China
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29
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An in vitro investigation of the actions of reproductive hormones on the cervix of the ewe in the follicular stage: the effects of 17β-estradiol, oxytocin, FSH, and arachidonic acid on the cervical pathway for the synthesis of prostaglandin E2. Theriogenology 2014; 83:1007-14. [PMID: 25586640 DOI: 10.1016/j.theriogenology.2014.12.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/11/2014] [Revised: 11/28/2014] [Accepted: 12/01/2014] [Indexed: 01/23/2023]
Abstract
During the periovulatory period, the cervix of the ewe relaxes and this mechanism is thought to be mediated by oxytocin and prostaglandin E2 (PGE2) in response to increased concentrations of 17β-estradiol and perhaps FSH. The aim of the study was to determine the in vitro effects of 17β-estradiol, FSH, oxytocin, and arachidonic acid (AA) on the synthesis of PGE2 and on the expression of oxytocin receptor (OTR), cytoplasmic phospholipase A2 (cPLA2), and cyclooxygenase 2 (COX-2) in explants of cervical tissue collected from ewes in the periovulatory phase of the estrous cycle. Cervical minces from ewes in the follicular phase of the estrous cycle were cultured in supplemented Eagle's Minimum Essential Medium for 48 hours with 17β-estradiol, FSH, oxytocin, or AA. After incubation, the tissue was stored at -80 °C and the media at -20 °C. Western immunoblotting was used to determine relative levels of OTR, cPLA2, and COX-2 in cervical tissue, and the media was analyzed by RIA, to determine the concentration of PGE2. The addition of 17β-estradiol increased the concentration of PGE2 in the media (P = 0.001), the levels of COX-2 (P = 0.02) and OTR (P = 0.006) but not those of cPLA2 (P = 0.15). The addition of FSH increased the levels of COX-2 (P = 0.01) but, it had no effect on the concentration of PGE2 (P = 0.08) or on the levels of OTR (P = 0.07) and cPLA2 (P = 0.15). Oxytocin did not increase the levels of COX-2 (P = 0.38) but increased those of OTR (P = 0.001) and cPLA2 (P = 0.01) but not on the concentration of PGE2 in the media. Arachidonic acid increased the levels of cPLA2 (P = 0.01) and those of COX-2 (P = 0.02) but not the concentration of PGE2 in the media. Our findings suggest that the PGE2-mediated mechanisms of cervical relaxation in the ewe during the follicular phase are stimulated by FSH, 17β-estradiol, oxytocin, and AA. They all appear to act by inducing receptors and enzymes along the synthetic pathway for PGE2.
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30
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Guerrero CA, Paula Pardo VR, Rafael Guerrero OA. Inhibition of rotavirus ECwt infection in ICR suckling mice by N-acetylcysteine, peroxisome proliferator-activated receptor gamma agonists and cyclooxygenase-2 inhibitors. Mem Inst Oswaldo Cruz 2014; 108:741-54. [PMID: 24037197 PMCID: PMC3970679 DOI: 10.1590/0074-0276108062013011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/10/2013] [Accepted: 06/21/2013] [Indexed: 01/01/2023] Open
Abstract
Live attenuated vaccines have recently been introduced for preventing rotavirus
disease in children. However, alternative strategies for prevention and
treatment of rotavirus infection are needed mainly in developing countries where
low vaccine coverage occurs. In the present work, N-acetylcysteine (NAC),
ascorbic acid (AA), some nonsteroidal anti-inflammatory drugs (NSAIDs) and
peroxisome proliferator-activated receptor gamma (PPARγ) agonists were tested
for their ability to interfere with rotavirus ECwt infectivity as detected by
the percentage of viral antigen-positive cells of small intestinal villi
isolated from ECwt-infected ICR mice. Administration of 6 mg NAC/kg every 8 h
for three days following the first diarrhoeal episode reduced viral infectivity
by about 90%. Administration of AA, ibuprofen, diclofenac, pioglitazone or
rosiglitazone decreased viral infectivity by about 55%, 90%, 35%, 32% and 25%,
respectively. ECwt infection of mice increased expression of cyclooxygenase-2,
ERp57, Hsc70, NF-κB, Hsp70, protein disulphide isomerase (PDI) and PPARγ in
intestinal villus cells. NAC treatment of ECwt-infected mice reduced Hsc70 and
PDI expression to levels similar to those observed in villi from uninfected
control mice. The present results suggest that the drugs tested in the present
work could be assayed in preventing or treating rotaviral diarrhoea in children
and young animals.
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31
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Wariki WMV, Goto Y, Ota E, Mori R. Cyclo-oxygenase (COX) inhibitors for threatened miscarriage. Hippokratia 2014. [DOI: 10.1002/14651858.cd011310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/11/2022]
Affiliation(s)
- Windy MV Wariki
- Manado State University; Department of Public Health; Unima Campus Tondano North Sulawesi Indonesia 95618
| | - Yoshihito Goto
- Kyoto University School of Public Health; Department of Health Informatics; Yoshida Konoecho, Sakyo-ku Kyoto Japan 606-8501
| | - Erika Ota
- National Center for Child Health and Development; Department of Health Policy; 2-10-1 Okura, Setagaya-ku Tokyo Japan 157-8535
| | - Rintaro Mori
- National Center for Child Health and Development; Department of Health Policy; 2-10-1 Okura, Setagaya-ku Tokyo Japan 157-8535
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Abstract
Preterm birth (PTB) is an important issue in neonates because of its complications as well as high morbidity and mortality. The prevalence of PTB is approximately 12-13% in USA and 5-9% in many other developed countries. China represents 7.8% (approximately one million) of 14.9 million babies born prematurely annually worldwide. The rate of PTB is still increasing. Both genetic susceptibility and environmental factors are the major causes of PTB. Inflammation is regarded as an enabling characteristic factor of PTB. The aim of this review is to summarize the current literatures to illustrate the role of single nucleotide polymorphisms (SNPs) of cytokine genes in PTB. These polymorphisms are different among different geographic regions and different races, thus different populations may have different risk factors of PTB. SNPs affect the ability to metabolize poisonous substances and determine inflammation susceptibility, which in turn has an influence on reproduction-related risks and on delivery outcomes after exposure to environmental toxicants and pathogenic organisms.
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Affiliation(s)
- Qin Zhu
- Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou 215002, China
| | - Jian Sun
- Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou 215002, China
| | - Ying Chen
- Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou 215002, China
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33
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Vromman A, Trabelsi N, Rouxel C, Béréziat G, Limon I, Blaise R. β-Amyloid context intensifies vascular smooth muscle cells induced inflammatory response and de-differentiation. Aging Cell 2013; 12:358-69. [PMID: 23425004 DOI: 10.1111/acel.12056] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 02/04/2013] [Indexed: 11/28/2022] Open
Abstract
Several studies have shown that the accumulation of β-amyloid peptides in the brain parenchyma or vessel wall generates an inflammatory environment. Some even suggest that there is a cause-and-effect relationship between inflammation and the development of Alzheimer's disease and/or cerebral amyloid angiopathy (CAA). Here, we studied the ability of wild-type Aβ1-40 -peptide (the main amyloid peptide that accumulates in the vessel wall in sporadic forms of CAA) to modulate the phenotypic transition of vascular smooth muscle cells (VSMCs) toward an inflammatory/de-differentiated state. We found that Aβ1-40 -peptide alone neither induces an inflammatory response, nor decreases the expression of contractile markers; however, the inflammatory response of VSMCs exposed to Aβ1-40 -peptide prior to the addition of the pro-inflammatory cytokine IL-1β is greatly intensified compared with IL-1β-treated VSMCs previously un-exposed to Aβ1-40 -peptide. Similar conclusions could be drawn when tracking the decline of contractile markers. Furthermore, we found that the mechanism of this potentiation highly depends on an Aβ1-40 preactivation of the PI3 Kinase and possibly NFκB pathway; indeed, blocking the activation of these pathways during Aβ1-40 -peptide treatment completely suppressed the observed potentiation. Finally, strengthening the possible in vivo relevance of our findings, we evidenced that endothelial cells exposed to Aβ1-40 -peptide generate an inflammatory context and have similar effects than the ones described with IL-1β. These results reinforce the idea that intraparietal amyloid deposits triggering adhesion molecules in endothelial cells, contribute to the transition of VSMCs to an inflammatory/de-differentiated phenotype. Therefore, we suggest that acute inflammatory episodes may increase vascular alterations and contribute to the ontogenesis of CAA.
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Affiliation(s)
- Amélie Vromman
- UR4, Vieillissement, Stress et Inflammation Université Paris 6 7 quai St‐Bernard75252Paris cedex 5 France
| | - Nesrine Trabelsi
- UR4, Vieillissement, Stress et Inflammation Université Paris 6 7 quai St‐Bernard75252Paris cedex 5 France
| | - Clotilde Rouxel
- UR4, Vieillissement, Stress et Inflammation Université Paris 6 7 quai St‐Bernard75252Paris cedex 5 France
| | - Gilbert Béréziat
- UR4, Vieillissement, Stress et Inflammation Université Paris 6 7 quai St‐Bernard75252Paris cedex 5 France
| | - Isabelle Limon
- UR4, Vieillissement, Stress et Inflammation Université Paris 6 7 quai St‐Bernard75252Paris cedex 5 France
| | - Régis Blaise
- UR4, Vieillissement, Stress et Inflammation Université Paris 6 7 quai St‐Bernard75252Paris cedex 5 France
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Guerrero CA, Guererero CA, Murillo A, Acosta O. Inhibition of rotavirus infection in cultured cells by N-acetyl-cysteine, PPARγ agonists and NSAIDs. Antiviral Res 2012; 96:1-12. [PMID: 22842004 DOI: 10.1016/j.antiviral.2012.06.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/08/2012] [Revised: 06/22/2012] [Accepted: 06/26/2012] [Indexed: 12/30/2022]
Abstract
Although the current rotavirus vaccines have shown good tolerance and significant efficacy, it would be useful to develop alternative or complementary strategies aimed at preventing or treating acute diarrhoeal disease caused by this viral agent. A variety of antiviral strategies other than vaccines have been assayed for rotavirus infection management. The recently demonstrated sensitivity of rotavirus infectivity to thiol/disulfide reagents prompted assays for screening drugs that potentially affect cellular redox reactions. MA104 or Caco-2 cells were inoculated with the rotavirus strains RRV, Wa, Wi or M69 and then incubated with different concentrations of drugs belonging to a selected group of 60 drugs that are currently used in humans for purposes other than rotavirus infection treatment. Eighteen of these drugs were able to inhibit rotavirus infectivity to different extents. A more systematic evaluation was performed with drugs that could be used in children such as N-acetylcysteine and ascorbic acid, in addition to ibuprofen, pioglitazone and rosiglitazone, all of which affecting cellular pathways potentially needed by the rotavirus infection process. Evidence is provided here that rotavirus infectivity is significantly inhibited by NAC in different cell-culture systems. These findings suggest that NAC has the potential to be used as a therapeutic tool for treatment and prevention of rotavirus disease in children.
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Affiliation(s)
- Carlos A Guerrero
- Departamento de Ciencias Fisiológicas, Facultad de Medicina-Instituto de Biotecnología, Universidad Nacional de Colombia, Bogotá, DC, Colombia.
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35
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Soloff MS, Jeng YJ, Izban MG, Sinha M, Luxon BA, Stamnes SJ, England SK. Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci 2011; 18:781-97. [PMID: 21795739 PMCID: PMC4051400 DOI: 10.1177/1933719111398150] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/07/2023]
Abstract
An important action of progesterone during pregnancy is to maintain the uterus in a quiescent state and thereby prevent preterm labor. The causes of preterm labor are not well understood, so progesterone action on the myometrium can provide clues about the processes that keep the uterus from contracting prematurely. Accordingly, we have carried out Affymetrix GeneChip analysis of progesterone effects on gene expression in immortalized human myometrial cells cultured from a patient near the end of pregnancy. Progesterone appears to inhibit uterine excitability by a number of mechanisms, including increased expression of calcium and voltage-operated K(+) channels, which dampens the electrical activity of the myometrial cell, downregulation of agents, and receptors involved in myometrial contraction, reduction in cell signal components that lead to increased intracellular Ca(2+) concentrations in response to contractile stimuli, and downregulation of proteins involved in the cross-linking of actin and myosin filaments to produce uterine contractions.
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Affiliation(s)
- Melvyn S. Soloff
- Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX, USA
| | - Yow-Jiun Jeng
- Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX, USA
| | - Michael G. Izban
- Department of Obstetrics and Gynecology, Meharry Medical College, Nashville, TN, USA
| | - Mala Sinha
- Department of Biochemistry and Molecular Biology, and the Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX, USA
| | - Bruce A. Luxon
- Department of Biochemistry and Molecular Biology, and the Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX, USA
| | - Susan J. Stamnes
- Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Sarah K. England
- Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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Brighton PJ, Rana S, Challiss RJ, Konje JC, Willets JM. Arrestins differentially regulate histamine- and oxytocin-evoked phospholipase C and mitogen-activated protein kinase signalling in myometrial cells. Br J Pharmacol 2011; 162:1603-17. [PMID: 21175586 DOI: 10.1111/j.1476-5381.2010.01173.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND AND PURPOSE The uterotonins oxytocin and histamine, mediate contractile signals through specific G protein-coupled receptors, a process which is tightly controlled during gestation to prevent preterm labour. We previously identified G protein-coupled receptor kinase (GRK)2 and GRK6 as respective cardinal negative regulators of histamine H(1) and oxytocin receptor signalling. GRK-mediated phosphorylation promotes arrestin recruitment, not only desensitizing receptors but activating an increasing number of diverse signalling pathways. Here we investigate potential roles that arrestins play in the regulation of myometrial oxytocin/histamine H(1) receptor signalling. EXPERIMENTAL APPROACH Endogenous arrestins2 and 3 were specifically depleted using RNA-interference in a human myometrial cell line and the consequences of this for G protein-coupled receptor-mediated signalling were assessed using Ca(2+) /inositol 1,4,5-trisphophate imaging and standard mitogen-activated protein kinase (MAPK) assays. KEY RESULTS Depletion of arrestin3, but not arrestin2 enhanced and prolonged H(1) receptor-stimulated Ca(2+) responses, whilst depletion of either arrestin increased oxytocin receptor responses. Arrestin3 depletion decreased H(1) receptor desensitization, whilst removal of either arrestin isoform was equally effective in preventing oxytocin receptor desensitization. Following arrestin3 depletion oxytocin-induced phospho-extracellular signal-regulated kinase1/2 signals were diminished and histamine-stimulated signals virtually absent, whereas depletion of arrestin2 augmented extracellular signal-regulated kinase1/2 responses to each agonist. Conversely, depletion of arrestin3 enhanced p38 signals to each agonist, whilst arrestin2 suppression increased oxytocin-, but not histamine-induced p38 MAPK responses. CONCLUSIONS AND IMPLICATIONS Arrestin proteins are key regulators of H(1) and oxytocin receptor desensitization, and play integral roles mediating uterotonin-stimulated MAPK-signalling. These data provide insights into the in situ regulation of these receptor subtypes and may inform pathophysiological functioning in preterm labour.
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Affiliation(s)
- Paul J Brighton
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester, UK
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Mittal P, Romero R, Tarca AL, Gonzalez J, Draghici S, Xu Y, Dong Z, Nhan-Chang CL, Chaiworapongsa T, Lye S, Kusanovic JP, Lipovich L, Mazaki-Tovi S, Hassan SS, Mesiano S, Kim CJ. Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term. J Perinat Med 2010; 38:617-43. [PMID: 20629487 PMCID: PMC3097097 DOI: 10.1515/jpm.2010.097] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022]
Abstract
AIMS to characterize the transcriptome of human myometrium during spontaneous labor at term. METHODS myometrium was obtained from women with (n=19) and without labor (n=20). Illumina HumanHT-12 microarrays were utilized. Moderated t-tests and false discovery rate adjustment of P-values were applied. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for a select set of differentially expressed genes in a separate set of samples. Enzyme-linked immunosorbent assay and Western blot were utilized to confirm differential protein production in a third sample set. RESULTS 1) Four hundred and seventy-one genes were differentially expressed; 2) gene ontology analysis indicated enrichment of 103 biological processes and 18 molecular functions including: a) inflammatory response; b) cytokine activity; and c) chemokine activity; 3) systems biology pathway analysis using signaling pathway impact analysis indicated six significant pathways: a) cytokine-cytokine receptor interaction; b) Jak-STAT signaling; and c) complement and coagulation cascades; d) NOD-like receptor signaling pathway; e) systemic lupus erythematosus; and f) chemokine signaling pathway; 4) qRT-PCR confirmed over-expression of prostaglandin-endoperoxide synthase-2, heparin binding epidermal growth factor (EGF)-like growth factor, chemokine C-C motif ligand 2 (CCL2/MCP1), leukocyte immunoglobulin-like receptor, subfamily A member 5, interleukin (IL)-8, IL-6, chemokine C-X-C motif ligand 6 (CXCL6/GCP2), nuclear factor of kappa light chain gene enhancer in B-cells inhibitor zeta, suppressor of cytokine signaling 3 (SOCS3) and decreased expression of FK506 binding-protein 5 and aldehyde dehydrogenase in labor; 5) IL-6, CXCL6, CCL2 and SOCS3 protein expression was significantly higher in the term labor group compared to the term not in labor group. CONCLUSIONS myometrium of women in spontaneous labor at term is characterized by a stereotypic gene expression pattern consistent with over-expression of the inflammatory response and leukocyte chemotaxis. Differential gene expression identified with microarray was confirmed with qRT-PCR using an independent set of samples. This study represents an unbiased description of the biological processes involved in spontaneous labor at term based on transcriptomics.
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Affiliation(s)
- Pooja Mittal
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, USA.
| | - Roberto Romero
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA,Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Adi L. Tarca
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA,Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA,Department of Computer Science, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Juan Gonzalez
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Sorin Draghici
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Computer Science, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Yi Xu
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA
| | - Zhong Dong
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA
| | - Chia-Ling Nhan-Chang
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Tinnakorn Chaiworapongsa
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Stephen Lye
- Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada
| | - Juan Pedro Kusanovic
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Leonard Lipovich
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA,Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Shali Mazaki-Tovi
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Sonia S. Hassan
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Sam Mesiano
- Department of Reproductive Biology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Chong Jai Kim
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, USA
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Terzidou V, Blanks AM, Kim SH, Thornton S, Bennett PR. Labor and inflammation increase the expression of oxytocin receptor in human amnion. Biol Reprod 2010; 84:546-52. [PMID: 20926803 DOI: 10.1095/biolreprod.110.086785] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/16/2023] Open
Abstract
The oxytocin/oxytocin receptor (OXT/OXTR) system plays an important role in the regulation of parturition. The amnion is a major source of prostaglandins and inflammatory cytokine synthesis, which increase both before and during labor. Amnion is a noncontractile tissue; therefore, the role played by OXT/OXTR in this tissue will be fundamentally different from the role played in myometrial contractions. In the present study, we demonstrate increased OXTR mRNA and protein concentrations in human amnion epithelial cells associated with the onset of labor. We show that incubation of primary human amnion epithelial cells with IL1B results in a rapid, transient up-regulation of OXTR mRNA expression, which peaks in prelabor samples after 6 h. Incubation of prelabor amnion epithelial cells with OXT results in a marked increase of prostaglandin E(2) synthesis, and we demonstrate that OXT activates the extracellular signal-regulated protein kinase signal transduction pathway to stimulate up-regulation of cyclo-oxygenase 2 in human amnion epithelial cells. The increased ability of human amnion to produce prostaglandins in response to OXT treatment suggests a complementary role for the OXT/OXTR system in the activation of human amnion and the onset of labor.
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Affiliation(s)
- Vasso Terzidou
- Imperial College London, Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, Du Cane Road, London, United Kingdom.
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Phillips RJ, Al-Zamil H, Hunt LP, Fortier MA, López Bernal A. Genes for prostaglandin synthesis, transport and inactivation are differentially expressed in human uterine tissues, and the prostaglandin F synthase AKR1B1 is induced in myometrial cells by inflammatory cytokines. Mol Hum Reprod 2010; 17:1-13. [PMID: 20595240 DOI: 10.1093/molehr/gaq057] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/13/2022] Open
Abstract
Prostaglandins (PGs) are important factors in the physiology of human parturition and the control of uterine contractility. We have characterized the expression of 15 genes from all stages of the PG pathway in human pregnant and non-pregnant (NP) myometrium and in other uterine tissues at delivery, and the results show patterns indicative of different capacities for PG synthesis and catabolism in each tissue. In placenta, the PG synthase expression profile favours production of PGD₂, PGE₂ and PGF₂, with high levels of PG transporters and catabolic PG dehydrogenase suggesting rapid PG turnover. Choriodecidua is primed for PGE₂, PGF₂ and PGD₂ production and high PG turnover, whereas amnion expresses genes for PGE₂ synthesis with low levels of PG transporters and dehydrogenase. In umbilical cord, PGI₂ synthase is highly expressed. In pregnant myometrium, PGI₂, PGD₂ and PGF₂ synthases are highly expressed, whereas PG dehydrogenase is underexpressed. Myometrium from women with spontaneous or induced labour had higher expression of the PGH₂ synthase PTGS2 than tissue from women not-in-labour. Myometrium from NP women had lower levels of PG synthases and higher levels of PG dehydrogenase than pregnant myometrium. Discriminant function analysis showed that expression of selected genes in myometrium could distinguish groups of women with different modes of labour from each other and from NP women. In cultured myometrial cells, there was a dose-dependent stimulatory effect of interleukin 1β and tumour necrosis factor α on PTGS2, PTGES and AKR1B1 (PGF synthase) expression.
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Affiliation(s)
- R J Phillips
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Clinical Science at South Bristol (Obstetrics and Gynaecology), University of Bristol, Dorothy Hodgkin Building, Bristol BS1 3NY, UK.
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40
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Equils O, Nambiar P, Hobel CJ, Smith R, Simmons CF, Vali S. A computer simulation of progesterone and Cox2 inhibitor treatment for preterm labor. PLoS One 2010; 5:e8502. [PMID: 20111699 PMCID: PMC2811723 DOI: 10.1371/journal.pone.0008502] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/26/2009] [Accepted: 11/11/2009] [Indexed: 12/05/2022] Open
Abstract
Background Sufficient information from in vitro and in vivo studies has become available to permit computer modeling of the processes that occur in the myometrium during labor. This development allows the in silico investigation of pathological mechanisms and the trialing of potential treatments. Methods/Results Based on the human literature, we developed a computer model of the immune-endocrine environment of the myometrial cell. The interactions between molecules are represented by differential equations. The model is designed to simulate the estrogen and progesterone receptor changes during pregnancy and particularly the changes in the progesterone receptor (PR) isoforms A and B that are thought to mediate functional progesterone withdrawal in the human at labor. Parturition is represented by an increase in the PRA to PRB ratio to levels seen in women in labor. Infection is shown by inducing inflammation in the system by increasing phospho-IkB kinase concentration (IKK) levels; which lead to increased NF-κB activation, causing an increase in the PRA/PRB ratio. We examined the effects of progesterone or cyclo-oxygenase 2 (Cox2) inhibitor treatments on the PRA/PRB ratio in silico. The model predicted that high doses of progesterone and Cox2 inhibition would be effective in preventing an NF-κB-induced PRA/PRB ratio increase to the levels found during labor. Conclusions Our data illustrate the use of dynamic biological computer simulations to test the effectiveness of therapeutic interventions. This may allow the early rejection of ineffective therapies prior to expensive field trials.
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Affiliation(s)
- Ozlem Equils
- Department of Pediatrics, Burns and Allen Research Institute, Cedars-Sinai Medical Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
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41
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Engineer N, Sooranna SR, Liang Z, Bennett PR, Johnson MR. Influence of extracellular matrix on cytokine stimulated pro-labour gene expression in human uterine myocytes. Reprod Sci 2008; 15:950-60. [PMID: 19050328 DOI: 10.1177/1933719108322439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/16/2022]
Abstract
Cellular function is modulated by the interaction with the extracellular matrix within the myometrium. We formed the hypothesis that the cytokine-stimulated pro-labour gene expression by human uterine smooth muscle cells would be increased by growing the cells on collagen-coated plates. Primary cultures of human uterine smooth muscle cells grown on uncoated plates and on plates coated with collagen were exposed to the inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta and interleukin-6) and assessed the messenger RNA expression of oxytocin receptor, interleukin-8, prostaglandin H synthase type-2 and prostaglandin F(2) alpha receptor. Basal pro-labour gene expression was unaffected by collagen coating and the response to the inflammatory cytokines was similar for oxytocin receptor and prostaglandin H synthase type-2, but appeared to be reduced for interleukin-8 and enhanced for FP. Collagen coating made no significant impact on basal integrin expression and interleukin-1beta induced phosphorylation of extracellular-regulated-kinase1/2 and RelA subunit of nuclear factor-kappa B (p65). We conclude that growing human uterine smooth muscle cells on collagen-coated plates may modulate the pro-labour gene response to the inflammatory cytokines.
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Affiliation(s)
- Neelam Engineer
- Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea & Westminster Hospital, London, UK.
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42
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Lee SMY, Cheung CY, Nicholls JM, Hui KPY, Leung CYH, Uiprasertkul M, Tipoe GL, Lau YL, Poon LLM, Ip NY, Guan Y, Peiris JSM. Hyperinduction of cyclooxygenase-2-mediated proinflammatory cascade: a mechanism for the pathogenesis of avian influenza H5N1 infection. J Infect Dis 2008; 198:525-35. [PMID: 18613795 DOI: 10.1086/590499] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/17/2022] Open
Abstract
The mechanism for the pathogenesis of H5N1 infection in humans remains unclear. This study reveals that cyclooxygenase-2 (COX-2) was strongly induced in H5N1-infected macrophages in vitro and in epithelial cells of lung tissue samples obtained during autopsy of patients who died of H5N1 disease. Novel findings demonstrated that COX-2, along with tumor necrosis factor alpha and other proinflammatory cytokines were hyperinduced in epithelial cells by secretory factors from H5N1-infected macrophages in vitro. This amplification of the proinflammatory response is rapid, and the effects elicited by the H5N1-triggered proinflammatory cascade are broader than those arising from direct viral infection. Furthermore, selective COX-2 inhibitors suppress the hyperinduction of cytokines in the proinflammatory cascade, indicating a regulatory role for COX-2 in the H5N1-hyperinduced host proinflammatory cascade. These data provide a basis for the possible development of novel therapeutic interventions for the treatment of H5N1 disease, as adjuncts to antiviral drugs.
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Affiliation(s)
- Suki M Y Lee
- Department of Microbiology, Siriraj Hospital, Bangkok, Thailand
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43
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Molloy ES, Morgan MP, Doherty GA, McDonnell B, Hilliard M, O'Byrne J, Fitzgerald DJ, McCarthy GM. Mechanism of basic calcium phosphate crystal-stimulated cyclo-oxygenase-1 up-regulation in osteoarthritic synovial fibroblasts. Rheumatology (Oxford) 2008; 47:965-71. [DOI: 10.1093/rheumatology/ken144] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/22/2023] Open
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44
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Abstract
Complex cytokine networks play an important role in a wide range of reproductive and pregnancy related processes. Here, we review the current knowledge concerning the impact of cytokines on uterine physiology and pathophysiology. Cytokines influence a range of uterine functions during the menstrual cycle, implantation, pregnancy and labour. The synergistic interactions between individual cytokines are intricate and dynamic, and modulated by pregnancy hormones. It is not surprising therefore, that perturbations to cytokine signalling are associated with adverse pregnancy outcomes, such as miscarriage, pre-eclampsia, preterm labour and foetal brain injury. Further insight into the complexity of cytokine networks will be required to develop novel therapeutic strategies for the treatment of cytokine imbalances in pregnancy.
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Affiliation(s)
- N M Orsi
- Perinatal Research Group, The YCR and Liz Dawn Pathology and Translational Sciences Centre, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK
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45
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Chevillard G, Derjuga A, Devost D, Zingg HH, Blank V. Identification of interleukin-1β regulated genes in uterine smooth muscle cells. Reproduction 2007; 134:811-22. [DOI: 10.1530/rep-07-0289] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/08/2022]
Abstract
We analyzed the response of uterine smooth muscle cells to interleukin-1β (IL-1β). We first showed that PHM1-31 myometrial cells, our cellular model, are contractile. To determine the molecular mechanisms of uterine smooth muscle cell activation by proinflammatory cytokines, we performed genechip expression array profiling studies of PHM1-31 cells in the absence and the presence of IL-1β. In total, we identified 198 known genes whose mRNA levels are significantly modulated (> 2.0-fold change) following IL-1β exposure. We confirmed the expression changes for selected genes by independent mRNA and protein analysis. The group of genes induced by IL-1β includes transcription factors and inflammatory response genes such as nuclear factor of κ light polypeptide gene enhancer in B-cells (NFκB), pentraxin-related gene (PTX3), and tumor necrosis factor α-induced protein 3/A20 (TNFAIP3/A20). We also found up-regulation of chemokines like C-X-C motif ligand 3 (CXCL3) and extracellular matrix remodeling signaling molecules like tenascin C (TNC). Our data suggest that IL-1β elicits the rapid activation of a cellular network of genes particularly implicated in inflammatory response that may create a cellular environment favorable for myometrial cell contraction. Our results provide novel insights into the mechanisms of uterine smooth muscle cell regulation and possibly infection-induced preterm labor.
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46
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Lappas M, Permezel M, Rice GE. Mitogen-Activated Protein Kinase Proteins Regulate LPS-Stimulated Release of Pro-inflammatory Cytokines and Prostaglandins from Human Gestational Tissues. Placenta 2007; 28:936-45. [PMID: 17433832 DOI: 10.1016/j.placenta.2007.02.009] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/23/2007] [Revised: 02/18/2007] [Accepted: 02/20/2007] [Indexed: 11/16/2022]
Abstract
The role of pro-inflammatory cytokines and prostaglandins in human labour is well established. Many of the mRNAs stabilised by the MAPK pathway encode inflammatory mediators, suggesting that this kinase pathway plays a major role in the regulation of inflammation. The aim of this study was to determine if the MAPK pathway regulates the inflammatory response in human gestational tissues. Placenta and fetal membranes (n=5) obtained from pregnant women undergoing Caesarean section before the onset of labour were exposed to LPS, and co-incubated in the absence or presence of 12.5, 25 and 50 microM U0126 (ERK 1/2 inhibitor), SB202190 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor). After 18 h incubation, tissues were collected and ERK 1/2, p38 MAPK, and JNK total and phosphorylated protein expression was assessed by ELISA and/or Western blotting. The incubation medium was collected and TNF-alpha, IL-1beta, IL-6, IL-8, PGE(2) and PGF(2alpha) release was quantified by ELISA. Treatment of placenta and fetal membranes with LPS activated all three MAPK proteins. Co-incubation with U0126, SP600125 and SB202190 significantly suppressed LPS-stimulated activation of ERK 1/2, JNK, and p38 MAPK, respectively. All cytokine and prostaglandin release was significantly suppressed by all concentrations of U0126. LPS-stimulated IL-6, TNF-alpha, PGE(2) and PGF(2alpha) release was significantly suppressed by treatment with all concentrations of SB202190, whereas ILS-stimulated IL-1beta release was only significantly inhibited in the presence of 50 microM SB202190 and there was no effect of SB202190 on LPS-stimulated IL-8 release. SP600125 significantly repressed LPS-stimulated release of IL-1beta and TNF-alpha at all concentrations, whereas LPS-stimulated IL-6, PGE(2) and PGF(2alpha) release were inhibited at 25 and 50 microM. In conclusion, the MAPK inhibitors used in this study demonstrated differential activity against a range of sequelae commonly associated with inflammation, supporting the therapeutic potential of MAPK inhibitors in pregnancy complications associated with an aberrant inflammatory response.
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Affiliation(s)
- M Lappas
- Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal Research Centre, 4th Floor, 163 Studley Road, Heidelberg 3084, Victoria, Australia.
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47
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Markovic D, Vatish M, Gu M, Slater D, Newton R, Lehnert H, Grammatopoulos DK. The onset of labor alters corticotropin-releasing hormone type 1 receptor variant expression in human myometrium: putative role of interleukin-1beta. Endocrinology 2007; 148:3205-13. [PMID: 17431005 DOI: 10.1210/en.2007-0095] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/05/2023]
Abstract
CRH targets the human myometrium during pregnancy. The efficiency of CRH actions is determined by expression of functional receptors (CRH-R), which are dynamically regulated. Studies in myometrial tissue biopsies using quantitative RT-PCR demonstrated that the onset of labor, term or preterm, is associated with a significant 2- to 3-fold increase in CRH-R1 mRNA levels. Detailed analysis of myometrial CRH-R1 mRNA variants showed a decline of the pro-CRH-R1 mRNA encoding the CRH-R1beta variant during labor and increased mRNA levels of CRH-R1d mRNA. Studies in myometrial cells identified IL-1beta as an important regulator of myometrial CRH-R1 gene expression because prolonged treatment of myometrial cells with IL-1beta (1 ng/ml) for 18 h induced expression of CRH-R1 mRNA levels by 1.5- to 2-fold but significantly attenuated CRH-R1beta mRNA expression by 70%. In contrast, IL-1beta had no effect on CRH-R1d mRNA expression. Studies using specific inhibitors suggest that ERK1/2, p38 MAPK, and downstream nuclear translocation of nuclear factor-kappaB mediate IL-1beta effects on myometrial CRH-R1 gene. However, the increased CRH-R1 mRNA expression was associated with a dampening of the receptor efficacy to activate the adenylyl cyclase/cAMP signaling cascade. Thus, our findings suggest that IL-1beta is an important regulator of CRH-R1 expression and functional activity, and this interaction might play a role in the transition of the uterus from quiescence to active contractions necessary for the onset of parturition.
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MESH Headings
- Blotting, Western
- Butadienes/pharmacology
- Cells, Cultured
- Coumarins/pharmacology
- Cyclic AMP/metabolism
- Cyclooxygenase 2/genetics
- Cyclooxygenase 2/metabolism
- Female
- Gene Expression/drug effects
- Gene Expression/genetics
- Humans
- I-kappa B Kinase/antagonists & inhibitors
- Imidazoles/pharmacology
- Interleukin-1beta/metabolism
- Interleukin-1beta/pharmacology
- Labor Onset/physiology
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Microscopy, Confocal
- Mitogen-Activated Protein Kinase 3/antagonists & inhibitors
- Myocytes, Smooth Muscle/cytology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Myometrium/cytology
- Myometrium/drug effects
- Myometrium/metabolism
- NF-kappa B/metabolism
- Nitriles/pharmacology
- Pregnancy
- Pyridines/pharmacology
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Corticotropin-Releasing Hormone/genetics
- Receptors, Corticotropin-Releasing Hormone/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction/drug effects
- p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
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Affiliation(s)
- Danijela Markovic
- Endocrinology and Metabolism, Warwick Medical School, The University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom
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48
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Dorrance AM. Interleukin 1-beta (IL-1beta) enhances contractile responses in endothelium-denuded aorta from hypertensive, but not normotensive, rats. Vascul Pharmacol 2007; 47:160-5. [PMID: 17602892 PMCID: PMC2000828 DOI: 10.1016/j.vph.2007.05.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/01/2006] [Revised: 05/14/2007] [Accepted: 05/31/2007] [Indexed: 11/20/2022]
Abstract
BACKGROUND The chronic effects of interleukin 1-beta (IL-beta) on vascular reactivity include augmentation of contraction and relaxation. Few studies have assessed the acute effects of IL-1beta in vessels from hypertensive and normotensive rats. We hypothesized that IL-1beta would enhance constriction in aorta from stroke prone spontaneously hypertensive rats (SHRSP). METHODS Endothelium denuded aortic rings from 12 week-old SHRSP and Wistar Kyoto (WKY) rats were mounted in a myograph and incubated with IL-1beta (20 ng/ml) for 1 h before construction of a phenylephrine dose response curve. Indomethacin (1 microM) and PP-2 (1 microM) were utilized to inhibit cyclooxygenase (COX) and Src-kinase respectively. RESULTS In aorta from SHRSP, IL-1beta caused a significant increase in the force generated over the hour incubation; inhibition of COX or Src-kinase prevented this. The maximum phenylephrine-induced contraction was greater in aorta from SHRSP incubated with IL-1beta than control. COX or Src-kinase inhibition prevented this. IL-1beta had no effect on the vessels from WKY rats. CONCLUSIONS These novel data suggest that IL-1beta has rapid effects on vascular smooth muscle from hypertensive rats to produce constriction and to enhance phenylephrine-induced constriction. The COX and Src-kinase pathways appear to be involved in this response.
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Affiliation(s)
- Anne M Dorrance
- Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000, USA.
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Abstract
Preterm labour continues to be a major contributor to neonatal and infant morbidity. Recent data from the USA indicate that the number of preterm deliveries (including those associated with preterm labour) has risen in the last 20 years by 30%. This increase is despite considerable efforts to introduce new therapies for the prevention and treatment of preterm labour and highlights the need to assess research in this area from a fresh perspective. In this paper we discuss i) the limitations of our knowledge concerning prediction, prevention and treatment of preterm labour and ii) future multidisciplinary strategies for improving our approach.
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Affiliation(s)
- Rachel Marie Tribe
- Maternal and Fetal Research Unit, Division of Reproduction and Endocrinology, King's College London, St, Thomas' Hospital Campus, London, UK.
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Astle S, Newton R, Thornton S, Vatish M, Slater DM. Expression and regulation of prostaglandin E synthase isoforms in human myometrium with labour. Mol Hum Reprod 2006; 13:69-75. [PMID: 17105783 DOI: 10.1093/molehr/gal093] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/20/2022] Open
Abstract
Since the controversies regarding the use of non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclo-oxygenase (COX)-2 antagonists for the treatment of preterm labour (PTL), more emphasis has been placed on investigating the terminal synthases involved in the production of prostaglandins (PGs) to allow more targeted therapy in PTL. Prostaglandin E(2) (PGE(2)) is synthesized by one of three enzymes, cytosolic prostaglandin E synthase (cPGES), microsomal PGES-1 (mPGES-1) and microsomal PGES-2 (mPGES-2). We have determined (i) the immuno-localization of all three PGES enzymes in lower segment pregnant human myometrium, (ii) the expression of PGES and COX-2 mRNA expression at term and preterm gestation with and without labour and (iii) the effect of interleukin (IL)-1beta on COX-2 and PGES mRNA and protein expression in human myometrial smooth muscle (HMSM) cell cultures. We show mPGES-1 protein located predominantly in myometrial and vascular smooth muscle cells (SMCs), whilst mPGES-2 protein is largely in stromal cells surrounding the SMC and cPGES is diffusely located throughout the myometrium. Expression of mPGES-2 mRNA increased with term labour and PTL and expression of COX-2 and mPGES-1 mRNA with term labour, whereas cPGES expression did not change. IL-1beta stimulated release of PGE(2) by HMSM cells and increased COX-2 and mPGES-1 mRNA and protein expression. Thus, COX-2 expression and mPGES-1 expression are co-ordinately up-regulated in lower segment myometrium with term labour and with IL-1beta treatment in HMSM cells.
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Affiliation(s)
- S Astle
- Clinical Sciences Research Institute, Warwick Medical School, UHCW Trust, Coventry, UK
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