Obstetrics and Gynaecology - Research Publications

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    Hepatitis A virus cellular receptor 2 (HAVCR2) is decreased with viral infection and regulates pro-labour mediators OA
    Liong, S ; Lim, R ; Barker, G ; Lappas, M (WILEY, 2017-07)
    PROBLEM: Intrauterine infection caused by viral infection has been implicated to contribute to preterm birth. Hepatitis A virus cellular receptor 2 (HAVCR2) regulates inflammation in non-gestational tissues in response to viral infection. METHOD OF STUDY: The aims of this study were to determine the effect of: (i) viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) on HAVCR2 expression; and (ii) HAVCR2 silencing by siRNA (siHAVCR2) in primary amnion and myometrial cells on poly(I:C)-induced inflammation. RESULTS: In human foetal membranes and myometrium, HAVCR2 mRNA and protein expression was decreased when exposed to poly(I:C). Treatment of primary amnion and myometrial cells with poly(I:C) significantly increased the expression and release of pro-inflammatory cytokines TNF, IL1A, IL1B and IL6; the expression of chemokines CXCL8 and CCL2; the expression and secretion of adhesion molecules ICAM1 and VCAM1; and PTGS2 and PTGFR mRNA expression and the release of prostaglandin PGF2α . This increase was significantly augmented in cells transfected with siHAVCR2. Furthermore, mRNA expression of anti-inflammatory cytokines IL4 and IL10 was significantly decreased. CONCLUSION: Collectively, our data suggest that HAVCR2 regulates cytokines, chemokines, prostaglandins and cell adhesion molecules in the presence of viral infection. This suggests a potential for HAVCR2 activators as therapeutics for the management of preterm birth associated with viral infections.
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    The immunoproteasome inhibitor ONX-0914 regulates inflammation and expression of contraction associated proteins in myometrium
    Liong, S ; Lim, R ; Nguyen-Ngo, C ; Barker, G ; Parkington, HC ; Lappas, M (WILEY, 2018-08)
    There are currently no effective treatments to prevent spontaneous preterm labor. The precise upstream biochemical pathways that regulate the transition between uterine quiescence during pregnancy and contractility during labor remain unclear. It is well known however that intrauterine inflammation, including infection, is commonly associated with preterm labor. In this study, we identified the immunoproteasome subunit low-molecular-mass protein (LMP)7 mRNA expression to be significantly upregulated in laboring human myometrium. Silencing LMP7 using siRNA-targeted knockdown of LMP7 and its inhibitor ONX-0914 in human myometrial cells and tissues decreased proinflammatory cytokines (IL-6), cell chemotaxis (CXCL8, CCL2 expression, and THP-1 migration), cell to cell adhesion (ICAM1 expression and myometrial adhesion), contraction-associated proteins (PTGS2, FP, PGE2, and PGF2α), as well as suppressing contractions in myometrial cells and in myometrial tissues obtained from laboring women. In addition, LMP7 silencing reduced NF-κB RelA activity. ONX-0914 alleviated inflammation (CCL3, CXCL1, PTGS2, and IL-6) in myometrium, placenta, fetal brain, amniotic fluid, and maternal serum induced by LPS in pregnant mice. Collectively, our data suggest a novel role for ONX-014 to suppress uterine activation and contractility associated with preterm labor.
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    Resveratrol ameliorates the chemical and microbial induction of inflammation and insulin resistance in human placenta, adipose tissue and skeletal muscle
    Tran, HT ; Liong, S ; Lim, R ; Barker, G ; Lappas, M ; Mogi, M (PUBLIC LIBRARY SCIENCE, 2017-03-09)
    Gestational diabetes mellitus (GDM), which complicates up to 20% of all pregnancies, is associated with low-grade maternal inflammation and peripheral insulin resistance. Sterile inflammation and infection are key mediators of this inflammation and peripheral insulin resistance. Resveratrol, a stilbene-type phytophenol, has been implicated to exert beneficial properties including potent anti-inflammatory and antidiabetic effects in non-pregnant humans and experimental animal models of GDM. However, studies showing the effects of resveratrol on inflammation and insulin resistance associated with GDM in human tissues have been limited. In this study, human placenta, adipose (omental and subcutaneous) tissue and skeletal muscle were stimulated with pro-inflammatory cytokines TNF-α and IL-1β, the bacterial product lipopolysaccharide (LPS) and the synthetic viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) to induce a GDM-like model. Treatment with resveratrol significantly reduced the expression and secretion of pro-inflammatory cytokines IL-6, IL-1α, IL-1β and pro-inflammatory chemokines IL-8 and MCP-1 in human placenta and omental and subcutaneous adipose tissue. Resveratrol also significantly restored the defects in the insulin signalling pathway and glucose uptake induced by TNF-α, LPS and poly(I:C). Collectively, these findings suggest that resveratrol reduces inflammation and insulin resistance induced by chemical and microbial products. Resveratrol may be a useful preventative therapeutic for pregnancies complicated by inflammation and insulin resistance, like GDM.
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    ATF3 is a negative regulator of inflammation in human fetal membranes
    Lim, R ; Barker, G ; Liong, S ; Nguyen-Ngo, C ; Tong, S ; Kaitu'u-Lino, T ; Lappas, M (W B SAUNDERS CO LTD, 2016-11)
    INTRODUCTION: Infection and inflammation stimulate pro-inflammatory cytokines, prostaglandins and matrix metalloproteinase (MMP)-9, which play a central role in myometrial contractions and rupture of fetal membranes. In human and mouse immune cells, activating transcription factor 3 (ATF3) is a negative regulator of inflammation. No studies have examined the role of ATF3 in human labour. METHODS: Primary amnion cells were used to determine the effect of interleukin (IL)-1β and the bacterial product fibroblast-stimulating lipopeptide (fsl-1) on ATF3 expression, and the effect of ATF3 siRNA on pro-labour mediators. ATF3 expression was assessed in fetal membranes from non-labouring and labouring women at term and preterm, and after preterm pre-labour rupture of membranes (PPROM). RESULTS: IL-1β and fsl-1 significantly increased ATF3 expression. Silencing ATF3 significantly increased IL-1β- or fsl-1-induced expression of pro-inflammatory cytokines (TNF-α, IL-1α, IL-1β, IL-6) and chemokines (IL-8 and monocyte chemoattractant protein-1 (MCP-1)); cyclooxygenase-2 (COX-2) mRNA expression and prostaglandin PGF2α release; and MMP-9 expression. ATF3 expression was decreased in fetal membranes with term labour. There was no effect of preterm labour or PPROM on ATF3 expression. DISCUSSION: ATF3 is a negative regulator of inflammation in human fetal membranes; in primary amnion cells, ATF3 expression is induced by IL-1β and fsl-1, and ATF3 silencing further exacerbates the inflammatory response when stimulated with these factors. Subsequently, ATF3 expression is decreased in fetal membranes after term labour and with preterm chorioamnionitis, conditions closely associated with inflammation and infection. Our data suggest that ATF3 may play a role in the terminal processes of human labour and delivery.
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    Endocan expression is increased in the placenta from obese women with gestational diabetes mellitus
    Murthi, P ; Sarkis, R ; Lim, R ; Nguyen-Ngo, C ; Pratt, A ; Liong, S ; Lappas, M (W B SAUNDERS CO LTD, 2016-12)
    INTRODUCTION: Endocan, a member of the proteoglycan family, is involved in a wide range of diseases including obesity and diabetes. The aim of this study was to determine the effect of (i) maternal obesity and gestational diabetes mellitus (GDM) on placental endocan expression; and (ii) endocan knockdown on markers of inflammation. METHODS: Endocan mRNA and protein expression was determined in human placenta from (i) lean and obese and normal glucose tolerant (NGT) pregnant women (n = 10 patients per group); and (ii) women with GDM and BMI-matched NGT women (n = 40 patients per group). Primary villous trophoblast cells and HUVECs were used to assess the effect of endocan siRNA knockdown on pro-inflammatory cytokines. RESULTS: There was no effect of maternal obesity on placental endocan expression. Further, endocan expression was not different between lean NGT and BMI-matched women with GDM. However, endocan mRNA and protein expression was significantly higher in placenta from obese women with GDM when compared to BMI-matched NGT women. Knockdown of endocan in villous trophoblast cells and HUVECs had no effect on infection- or inflammation-induced expression and secretion of IL-6, IL-8 and MCP-1. DISCUSSION: Endocan expression is increased in the human placenta from obese women with GDM, and in response to pro-inflammatory stimuli. Loss-of-function studies in villous trophoblast cells and HUVECs revealed that endocan is not directly involved in the genesis or in the expression of pro-inflammatory cytokines induced by LPS or IL-1β. Further studies are required to elucidate the functional consequences of increased placental endocan expression in obese GDM pregnancies.
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    The Transcription Factor Interferon Regulatory Factor-1 (IRF1) Plays a Key Role in the Terminal Effector Pathways of Human Preterm Labor
    Lim, R ; Ha, TT ; Liong, S ; Barker, G ; Lappas, M (OXFORD UNIV PRESS INC, 2016-02-01)
    Preterm birth is the largest single cause of neonatal death and morbidity. By activating cytokine- and Toll-like receptor (TLR)-signaling pathways, infection and/or inflammation are strongly associated with preterm delivery. Interferon regulatory factor-1 (IRF1) is an important regulator of the inflammatory response. The aims of this study were to establish the effect of 1) labor on IRF1 expression in human fetal membranes and myometrium, 2) prolabor mediators on IRF1 expression and activity, and 3) IRF1 small interfering RNA on the expression of prolabor mediators. IRF1 expression was higher in fetal membranes and myometrium after spontaneous term labor and in preterm fetal membranes with infection. The proinflammatory cytokine IL1B, the bacterial product fsl-1, and viral analog polyinosinic:polycytidylic acid (poly [I:C]) significantly increased IRF1 mRNA expression and transcriptional activity in human primary myometrial cells. In addition, IL1B increased IRF1 activity in primary amnion cells. IRF1 silencing in myometrial cells decreased IL1B-, fsl-1-, and poly (I:C)-induced cytokine (IL6, TNF, IL1B) and chemokine (CXCL8, CCL2) mRNA expression and IL6, CXCL8, and CCL2 release. IL1B-, fsl-1-, and poly (I:C)-induced PTGS2 mRNA expression and IL1B-induced prostaglandin release was also decreased by IRF1 silencing. In conclusion, IRF1 upregulation in fetal membranes and myometrium after term labor indicates a proinflammatory role for IRF1 in human parturition. IRF1 is involved in TLR- and cytokine-mediated signaling in human myometrium. These data provide new insights into the mechanisms associated with inflammation- and infection-associated preterm birth. IRF1 inhibitors as therapeutics for the management of spontaneous preterm birth warrants further investigation.
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    Slit2 is decreased after spontaneous labour in myometrium and regulates pro-labour mediators
    Lim, R ; Liong, S ; Barker, G ; Lappas, M (ELSEVIER IRELAND LTD, 2014-12)
    Preterm birth, a global healthcare problem, is commonly associated with inflammation. As Slit2 plays an emerging role in inflammation, the purpose of this study was to determine the effect of Slit2 on labour mediators in human gestational tissues. Slit2 mRNA and protein expression were assessed using qRT-PCR and immunohistochemistry in foetal membranes and myometrium obtained before and after labour. Slit2 silencing was achieved using siRNA in primary myometrial cells. Pro-inflammatory and pro-labour mediators were evaluated by qRT-PCR, ELISA and gelatin zymography. Slit2 mRNA and protein expression were found to be significantly lower in myometrium after labour onset. There was no effect of term or preterm labour on Slit2 expression in foetal membranes. Slit2 mRNA expression was decreased in myometrium treated with LPS and IL-1β. Slit2 siRNA in myometrial cells increased IL-1β-induced pro-inflammatory cytokine gene expression and release (IL-6 and IL-8), COX-2 expression and prostaglandin PGE2 and PGF2α release, and MMP-9 gene expression and pro MMP-9 release. There was no effect of Slit2 siRNA on IL-1β-induced NF-κB transcriptional activity. Our results demonstrate that Slit2 is decreased in human myometrium after labour and our knock-down studies describe an anti-inflammatory effect of Slit2 in myometrial cells.