Vikki M Abrahams

Yale-New Haven Hospital, New Haven, Connecticut, United States

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Publications (98)352.78 Total impact

  • Placenta 04/2015; 36(4):504-505. DOI:10.1016/j.placenta.2015.01.499 · 3.29 Impact Factor
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    ABSTRACT: Objective: To investigate whether elevated IFN-α early in pregnancy is associated with poor pregnancy outcomes and examine its relationship to angiogenic imbalance. Methods: Women were enrolled in a case-control longitudinal study of lupus pregnancies. Serum samples obtained monthly through pregnancy were assayed for IFN-α and for antiangiogenic factor, sFlt1, and proangiogenic factor, (PlGF). Each of 28 SLE patients with poor pregnancy outcome was matched to an SLE patient with an uncomplicated pregnancy and to a pregnant healthy control. The effects of IFN-α and/or sFlt1on human endothelial cells and endothelial-trophoblast interactions was assessed. Results: Compared to SLE patients with uncomplicated pregnancies, patients with preeclampsia had increased IFN-α before clinical symptoms. Non-autoimmune patients destined for preeclampsia did not have increased IFN-α. In SLE patients with low IFN-α, marked angiogenic imbalance (higher sFlt1, lower PlGF and higher sFlt1/PlGF ratios) precedes maternal manifestations of preeclampsia, whereas in SLE with high IFN-α, preeclampsia occurs without evidence of systemic angiogenic imbalance. Treatment of human endothelial cells with sFlt1 induced expression of sFlt1 mRNA, and IFN-α dramatically amplified responses to sFlt1. In a model of spiral artery transformation, only IFN-α and sFlt1 together disrupted the ability of trophoblast cells to remodel endothelial tube structures. Conclusions: Our studies identify a new mechanism by which IFN-α induces an antiangiogenic milieu, increases the sensitivity of endothelial cells to sFlt1, and suggest that elevated IFN-α may contribute to pathogenesis of preeclampsia in some SLE pregnancies. This article is protected by copyright. All rights reserved. Copyright © 2015 American College of Rheumatology. PMID: 25603823 [PubMed - as supplied by publisher]
    Arthritis & Rheumatology 01/2015; 67(4). DOI:10.1002/art.39029 · 7.87 Impact Factor
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    ABSTRACT: ProblemThrombophilia is associated with pregnancy complications. Treatment with low molecular weight heparin (LMWH) improves pregnancy outcome, but the underlying mechanisms are not clear.Methods of studyWe analyzed Treg frequency in blood from thrombophilic pregnancies treated with LMWH (n = 32) or untreated (n = 33) and from healthy pregnancies (n = 39) at all trimesters. Additionally, we treated pregnant wild-type, heterozygous and homozygous factor-V-Leiden (FVL) mice with LMWH or PBS and determined Treg frequency, pro-/anti-inflammatory cytokine levels and Caspase-3-activity in placenta and decidua.ResultsTreg frequencies were increased in second and third trimester in LMWH-treated thrombophilic pregnancies compared to controls. Treg levels were comparable to those of normal pregnancies. Homozygous FVL mice had decreased decidual Tregs compared to wild-type mice. LMWH treatment normalized Tregs and was associated with increased decidual IL-10 mRNA. LMWH diminished Caspase-3-activity in mice of all genotypes.Conclusion We demonstrated anti-apoptotic and anti-inflammatory effects of LMWH in pregnant FVL mice. LMWH increased Treg levels in mice and humans, which suggests benefits of LMWH treatment for thrombophilic women during pregnancy.
    American Journal Of Reproductive Immunology 12/2014; 73(5). DOI:10.1111/aji.12348 · 3.32 Impact Factor
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    ABSTRACT: There is growing interest in the role of viral infections and their association with adverse pregnancy outcomes. While the trophoblast is permissive to viruses, little is still known about their impact on the placenta. We previously established that viral single stranded RNA (ssRNA), a Toll-like receptor 8 (TLR8) agonist, induces a restricted pro-inflammatory cytokine/chemokine response by upregulating the secretion of IL-6 and IL-8. In parallel the type I interferon, IFNbeta, is produced and acts back on the cell in an autocrine/paracrine manner to trigger caspase-3-dependent apoptosis. In this current study, we sought to extend these findings by determining the mechanisms involved, whether viral ssRNA could induce a trophoblast antiviral response, and to evaluate the influence of viral ssRNA on pregnancy outcome using a mouse model. Herein we report that viral ssRNA induced human first trimester trophoblast inflammation, type I IFN production, an antiviral response and apoptosis in both a TLR8/MyD88-dependent and -independent manner. Furthermore, administration of viral ssRNA to pregnant mice induced placental caspase-3 activation, a pro-inflammatory cytokine/chemokine, type I IFN, and antiviral response, as well as immune cell infiltration. Thus, ssRNA viral infections may compromise pregnancy by altering placental trophoblast survival and function through both TLR8 and non-TLR8 signaling pathways, leading to immune changes at the maternal-fetal interface. Copyright 2014 by The Society for the Study of Reproduction.
    Biology of Reproduction 11/2014; DOI:10.1095/biolreprod.114.124032 · 3.45 Impact Factor
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    ABSTRACT: ProblemDiabetes confers an increased risk of preeclampsia, but its pathogenic role in preeclampsia is poorly understood. The objective of this study was to elucidate the effects of excess glucose on trophoblast function and whether any changes could be reversed by metformin.Method of studyThe human first trimester trophoblast cell line (Sw.71) was treated with glucose at 5, 10, 25, and 50 mm, in the presence and absence of metformin. Trophoblast migration was quantified and supernatant cytokine, chemokine, and angiogenic factors measured.ResultsIncreasing concentrations of glucose significantly increased trophoblast secretion of the inflammatory cytokines/chemokines: IL-1β, IL-6, IL-8, GRO-, RANTES, and G-CSF; significantly increased trophoblast secretion of the anti-angiogenic factors sFlt-1 and sEndoglin; and significantly decreased trophoblast migration. Excess glucose-induced trophoblast IL-1β production was inhibited by disabling the Nalp3/ASC inflammasome. Metformin partially reduced the glucose-induced inflammatory response, but had no effect on the anti-angiogenic or antimigratory response.Conclusion Excess glucose induced a pro-inflammatory, anti-angiogenic, and antimigratory state in first trimester trophoblast cells. Glucose-induced trophoblast IL-1β secretion was mediated by the inflammasome. Glucose-induced inflammation was partially reversed by metformin. These findings demonstrate the pleiotropic effects of hyperglycaemia on the trophoblast, providing potential explanations for the strong link between diabetes and preeclampsia.
    American Journal Of Reproductive Immunology 11/2014; DOI:10.1111/aji.12339 · 3.32 Impact Factor
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    ABSTRACT: Objective Antiphospholipid antibodies (aPL) interfere with several physiologic functions of human trophoblasts, including reducing their ability to migrate, decreasing their production of angiogenic factors, and inducing an inflammatory response. This may provide the underlying mechanism by which aPL responses lead to recurrent pregnancy loss or preeclampsia in women with obstetric antiphospholipid syndrome (APS). Although treatment with heparin may reduce the rate of recurrent pregnancy loss, the risk of preeclampsia remains high. Therefore, alternative treatments are needed for the management of pregnant patients with APS. Since aspirin-triggered lipoxins (ATLs) have immune and angiogenic modulatory properties, the objective of this study was to determine the effects of the ATL 15-epi-lipoxin A4 on the function of aPL-altered human trophoblasts in the first trimester of pregnancy.MethodsA first-trimester human trophoblast cell line (HTR8) was treated with mouse anti-human β2-glycoprotein I monoclonal antibodies (aPL) in the presence or absence of the ATL 15-epi-lipoxin A4. Trophoblast migration and interactions with endometrial endothelial cells were measured using Transwell and coculture assays. Trophoblast secretion of cytokines and angiogenic factors was measured by enzyme-linked immunosorbent assay.ResultsTreatment of HTR8 cells with ATL reversed the aPL-induced decrease in trophoblast migration, an effect that appeared to be regulated through restoration of interleukin-6 production. Using a model of spiral artery transformation, aPL and sera from APS patients with pregnancy morbidity disrupted trophoblast-endothelial cell interactions, and treatment with ATL restored the stability of the cocultures. In contrast, ATL treatment did not resolve the proinflammatory and antiangiogenic responses of trophoblasts induced by aPL.Conclusion These findings indicate that ATLs may have some benefits in terms of preventing the effects of aPL on trophoblast function, which raises the possibility of the use of ATLs as an adjuvant therapy in women with aPL.
    10/2014; 67(2). DOI:10.1002/art.38934
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    ABSTRACT: ProblemMicrobial-driven responses in placenta are linked with adverse pregnancy outcomes. The role of Toll-like receptor (TLR) function in Hofbauer cells (HBCs) and fetal macrophages of the placental villous core remains understudied.Method of StudyFlow cytometry and immunohistochemistry (IHC) were used to establish the phenotype of HBCs. Regulation of cytokine secretion in response to treatment with TLR agonists and expression levels of TLRs and co-activators were compared in HBCs, placental fibroblasts (FIBs), and human umbilical vein endothelial cells (HUVECs) using ELISA and qPCR.ResultsAlthough flow cytometry and IHC revealed HBCs to be M2 (anti-inflammatory) macrophages, LPS and polyinosinic: polycytidylic acid [poly (I:C)] treatments markedly enhanced IL-6 secretion by HBCs, and expression of TLR-2, TLR-3, TLR-4, CD14, and MD-2 was the highest in HBCs.Conclusion These results indicate that although HBCs are M2 macrophages, inflammatory responses are induced through TLR-3 and TLR-4 in this cell type, suggesting a role in microbial-driven placental/fetal inflammation.
    American Journal Of Reproductive Immunology 10/2014; DOI:10.1111/aji.12336 · 3.32 Impact Factor
  • Geburtshilfe und Frauenheilkunde 09/2014; 74(S 01). DOI:10.1055/s-0034-1388030 · 0.96 Impact Factor
  • Placenta 09/2014; 35(9):A6. DOI:10.1016/j.placenta.2014.06.022 · 3.29 Impact Factor
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    ABSTRACT: ProblemWomen with antiphospholipid syndrome (APS) are at increased risk of recurrent pregnancy loss (RPL) and preeclampsia. Antiphospholipid antibodies (aPL) directly alter trophoblast function. Treatment with low molecular weight heparin (LMWH) reduces the risk of RPL but not preeclampsia. Moreover, LMWH stimulates trophoblast sFlt-1 release, an anti-angiogenic factor associated with preeclampsia. Since vitamin D deficiency is associated with APS and preeclampsia, this study sought to determine the effect of vitamin D on trophoblast function in the setting of aPL and LMWH.Method of studyA human first trimester trophoblast cell line (HTR8) and primary trophoblast cultures were treated with or without aPL in the presence and absence of vitamin D, LMWH or both. Trophoblast secretion of inflammatory cytokines and angiogenic factors were measured by ELISA.ResultsVitamin D alone or in combination with LMWH attenuated the aPL-induced trophoblast inflammatory response in the HTR8 cells and primary cultures. While vitamin D did not have any impact on aPL-mediated modulation of angiogenic factors in the primary trophoblast, it significantly inhibited LMWH-induced sFlt-1 release.ConclusionLMWH in combination with vitamin D may be more beneficial than single-agent therapy by preventing aPL-induced trophoblast inflammation and reversing LMWH-induced sFlt-1 secretion.
    American Journal Of Reproductive Immunology 07/2014; 73(3). DOI:10.1111/aji.12301 · 3.32 Impact Factor
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    ABSTRACT: Problem Inflammation during pregnancy has devastating consequences for the placenta and fetus. These events are incompletely understood, thereby hampering screening and treatment. Method of studyThe inflammatory profile of villous tissue was studied in pregnancies at high-risk of placental dysfunction and compared to uncomplicated pregnancies. The systemic inflammatory profile was assessed in matched maternal serum samples in cases of reduced fetal movements (RFM). ResultsPlacentas from RFM pregnancies had a unique inflammatory profile characterized by increased interleukin (IL)-1 receptor antagonist and decreased IL-10 expression, concomitant with increased numbers of placental macrophages. This aberrant cytokine profile was evident in maternal serum in RFM, as were increased levels of alarmins (uric acid, HMGB1, cell-free fetal DNA). Conclusion This distinct inflammatory profile at the maternal-fetal interface, mirrored in maternal serum, could represent biomarkers of placental inflammation and could offer novel therapeutic options to protect the placenta and fetus from an adverse maternal environment.
    American journal of reproductive immunology (New York, N.Y.: 1989) 05/2014; 72(4). DOI:10.1111/aji.12274 · 2.67 Impact Factor
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    ABSTRACT: There has been growing interest in the role of viral infections and their association with adverse pregnancy outcomes. However, little is known about the impact viral infections have on the fetal membranes (FM). Toll-like receptors (TLR) are thought to play a role in infection-associated inflammation at the maternal-fetal interface. Therefore, the objective of this study was to characterize the cytokine profile and antiviral response in human FMs exposed to viral dsRNA, which activates TLR3, and viral ssRNA, which activates TLR8; and to determine the mechanisms involved. The viral dsRNA analog, Poly(I:C), induced upregulated secretion of MIP-1α, MIP-1β, RANTES and TNF-α, and downregulated IL-2 and VEGF secretion. In contrast, viral ssRNA induced a broader panel of cytokines in the FMs by upregulating the secretion of IL-1β, IL-2, IL-6, G-CSF, MCP-1, MIP-1α, MIP-1β, RANTES, TNF-α and GRO-α. Using inhibitory peptides against TLR adapter proteins, FM secretion of MIP-1β and RANTES in response to Poly(I:C) was MyD88-dependent; MIP-1α secretion was dependent on MyD88 and TRIF; and TNF-α production was independent of MyD88 and TRIF. Viral ssRNA-induced FM secretion of IL-1β, IL-2, IL-6, G-CSF, MIP-1α, RANTES and GRO-α was dependent on MyD88 and TRIF; MIP-1β was dependent upon TRIF, but not MyD88; and TNF-α and MCP-1 secretion was dependent on neither. Poly(I:C), but not ssRNA, induced a FM antiviral response by upregulating the expression of inflammasome components, IFNβ, MxA, OAS and APOBEC3G. These findings demonstrate that human FMs respond to two viral signatures by generating distinct inflammatory cytokine/chemokine profiles and antiviral responses through different mechanisms.
    Molecular Human Reproduction 04/2014; DOI:10.1093/molehr/gau028 · 3.48 Impact Factor
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    ABSTRACT: Bacterial infection-associated inflammation is thought to be a major cause of preterm premature rupture of membranes (PPROM). Pro-inflammatory cytokines, such as IL1B, can weaken the fetal membranes (FM) by upregulating matrix metalloproteinases and inducing apoptosis. The mechanism by which infection leads to inflammation at the maternal-fetal interface and subsequent preterm birth is thought to involve innate immune pattern recognition receptors (PRR), such as the Toll-like receptors (TLR) and Nod-like receptors (NLR) which recognize pathogen-associated molecular patterns (PAMPs). The objective of this study was to determine the cytokine profile generated by FMs in response to the following bacterial TLR and NLR agonists: peptidoglycan (PDG; TLR2); lipopolysaccharide (LPS; TLR4); flagellin (TLR5); CpG ODN (TLR9); iE-DAP (Nod1) and MDP (Nod2). PDG, LPS, Flagellin, iE-DAP and MDP triggered FMs to generate an inflammatory response, however, the cytokine profiles were distinct for each TLR and NLR agonist; and only IL1B and RANTES were commonly upregulated in response to all five PAMPs. CpG ODN, in contrast, had a mild stimulatory effect only on MCP-1, and primarily downregulated basal FM cytokine production. IL1B secretion induced by PDG, LPS, flagellin, iE-DAP and MDP was associated with its processing. Furthermore, FM IL1B secretion in response to TLR2, TLR4 and TLR5 activation was caspase-1 dependent, while Nod1 and Nod2 induced IL1B secretion independent of caspase-1. These findings demonstrate that FMs respond to different bacterial TLR and NLR PAMPs by generating distinct inflammatory cytokine profiles through distinct mechanisms that are specific to the innate immune PRR activated.
    Biology of Reproduction 01/2014; 90(2). DOI:10.1095/biolreprod.113.115428 · 3.45 Impact Factor
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    ABSTRACT: Women with antiphospholipid syndrome (APS) are at risk for pregnancy complications. Antiphospholipid antibodies (aPL) alter trophoblast function by triggering an inflammatory cytokine response; modulating angiogenic factor secretion; and inhibiting migration. While patients with APS are often treated with hydroxychloroquine (HCQ), its effect on trophoblast function is poorly understood. A human first trimester trophoblast cell line was treated with or without antihuman β2 GPI mAbs in the presence or absence of HCQ. Supernatants were analyzed by ELISA. Cell migration was measured using a colormetric assay. Antiphospholipid antibodies-induced trophoblast IL-8, IL-1 β, PlGF, and sEndoglin secretion were not altered by HCQ. aPL-induced inhibition of trophoblast migration was partially reversed by HCQ, even though HCQ significantly increased secretion of pro-migratory IL-6 to greater than baseline. aPL-induced upregulation of TIMP2 appears to inhibit trophoblast migration; the inability of HCQ to prevent aPL-induced TIMP2 may explain why migration was only partially restored. Hydroxychloroquine reversed the aPL-inhibition of trophoblast IL-6 secretion and partially limited aPL-inhibition of cell migration. Thus, some form of combination therapy that includes HCQ may be beneficial to pregnant APS patients.
    American Journal Of Reproductive Immunology 12/2013; DOI:10.1111/aji.12184 · 3.32 Impact Factor
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    Manish Garg, Julie A Potter, Vikki M Abrahams
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    ABSTRACT: While infection-induced placental inflammation is a common mechanism of adverse pregnancy outcome, some pathogens can also trigger placental apoptosis, and Toll-like receptors (TLRs) mediate this response. Treatment of human first trimester trophoblast cells with bacterial peptidoglycan (PDG) reduces their constitutive secretion of IL-6 protein and induces apoptosis. This apoptotic response is dependent upon the cell's expression of TLR1, TLR2 and TLR10, and their lack of TLR6, such that ectopic expression of TLR6 prevents PDG-induced apoptosis and restores IL-6 production. In this current study we have identified three microRNAs (miRs) that regulate TLR2-mediated responses in the human trophoblast. Herein we report that miR-329 plays a pivotal role in mediating PDG-induced trophoblast apoptosis and inhibition of IL-6 mRNA expression by targeting the NF-κB subunit, p65. TLR2 activation by PDG upregulates miR-329 expression and inhibits NF-κB p65 and IL-6 mRNA, and this is reversed by the presence of TLR6. Moreover, inhibition of miR-329 prevents PDG-induced inhibition of NF-κB p65 and IL-6 mRNA expression, and restores cell survival. In addition, we have found miR-23a and let-7c to directly regulate PDG-mediated inhibition of IL-6 mRNA. TLR2 activation by PDG upregulates miR23a and let-7c expression and this is reversed by the presence of TLR6. Furthermore, inhibition of both miR23a and let-7c prevents PDG-inhibition of trophoblast IL-6 mRNA expression. Together, our findings suggest that multiple miRs are involved in the molecular regulation of TLR2-mediated responses in the trophoblast towards gram-positive bacterial components.
    PLoS ONE 10/2013; 8(10):e77249. DOI:10.1371/journal.pone.0077249 · 3.53 Impact Factor
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    ABSTRACT: Women with antiphospholipid syndrome (APS) are at risk of recurrent pregnancy loss and obstetrical disorders, such as preeclampsia and intrauterine growth restriction (IUGR). Antiphospholipid antibodies (aPL) directly target the placenta by binding beta2-glycoprotein I (β2GPI) expressed on the trophoblast. We recently demonstrated in human first trimester trophoblast cells that anti-β2GPI antibodies (Abs) induce the secretion of IL-1β in a Toll-like receptor 4 (TLR4)-dependent manner. IL-1β secretion requires processing of pro-IL-1β and this is mediated by the inflammasome, a complex of Nalp3, apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1. The objective of this study was to determine if aPL induce IL-1β production in trophoblast via the inflammasome. Using a human first trimester trophoblast cell line, we demonstrated that a mouse anti-β2GPI mAb and human polyclonal aPL-IgG induce IL-1β processing and secretion, which was partially blocked upon caspase-1 inhibition. Nalp3 and ASC knockdown also attenuated anti-β2GPI Ab-induced IL-1β secretion. Furthermore, aPL stimulated the production of uric acid in a TLR4-dependent manner; and inhibition of uric acid prevented aPL-induced IL-1β production by the trophoblast. These findings demonstrate that aPL, via TLR4 activation, induce a uric acid response in human trophoblast, which in turn activates the Nalp3/ASC inflammasome leading to IL-1β processing and secretion. This novel mechanism may account for the inflammation at the maternal-fetal interface, which causes placental dysfunction and increases the risk of adverse pregnancy outcome in patients with APS.
    PLoS ONE 06/2013; 8(6):e65237. DOI:10.1371/journal.pone.0065237 · 3.53 Impact Factor
  • Graciela Krikun, Julie A Potter, Vikki M Abrahams
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    ABSTRACT: PROBLEM: Human endometrial endothelial cell (HEEC) innate immunity remains poorly characterized. Based on their direct contact with the circulation, HEECs are uniquely positioned to be exposed to viral infections. This study evaluated the innate immune response generated by HEECs after exposure to the TLR3 agonist, Poly(I:C) and the TLR8 agonist, viral ssRNA. METHOD OF STUDY: HEECs were treated with or without Poly(I:C) or ssRNA. Culture supernatants were measured for cytokines by multiplex analysis. RNA was analyzed by qRT-PCR for type I interferons and antiviral factors. RESULTS: Treatment of HEECs with Poly(I:C) rapidly upregulated the secretion of IL-2, IL-6, IL-8, IFN-γ, G-CSF, GM-CSF, MCP-1, MIP-1β, RANTES, and GRO-α after 12 hr, while ssRNA treatment induced the slower secretion of IL-6, IL-8, IFN-γ, G-CSF, VEGF, and GRO-α after 24 hr. Both viral components induced HEEC IFN-α and IFN-β expression. While treatment with Poly(I:C) induced APOBEC3G and OAS expression, treatment with ssRNA upregulated APOBEC3G and M×A mRNA. CONCLUSION: Our findings demonstrate that HEECs can differentially sense and respond to viral components by generating distinct inflammatory and antiviral immune responses, indicating that these cells likely play an active role in the immune protection of the uterus toward viral infections.
    American Journal Of Reproductive Immunology 04/2013; 70(3). DOI:10.1111/aji.12128 · 3.32 Impact Factor
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    ABSTRACT: PROBLEM: There is a strong correlation between intrauterine bacterial infection and preterm labor. While inflammation is a common mechanism, certain pathogens may trigger placental apoptosis. TLR2 activation by gram-positive bacterial peptidoglycan (PDG) induces first-trimester trophoblast apoptosis and decreased IL-6 secretion. This is dependent upon the presence of TLR1 and the absence of TLR6 and both TLR2 coreceptors. As TLR10 is also a TLR2 coreceptor, the objective of this study was to determine its expression and function in the trophoblast. METHOD OF STUDY: First-and third-trimester human placental tissue and isolated trophoblast were evaluated for TLR10 expression. A first-trimester human trophoblast cell line stably transfected with a TLR10 dominant negative (TLR10-DN) or vector control was treated with or without PDG and analyzed for apoptosis and IL-6. RESULTS: TLR10 was expressed by trophoblasts during the first and third trimesters of pregnancy. PDG-induced trophoblast caspase-3 activity was inhibited by the presence of the TLR10-DN. The presence of the TLR10-DN had no effect on PDG reduction in trophoblast IL-6 secretion. CONCLUSION: This study demonstrates that trophoblast TLR10 plays a role in promoting apoptosis triggered by gram-positive bacterial components and suggests that TLR10 may regulate the balance between trophoblast survival and cell death.
    American Journal Of Reproductive Immunology 12/2012; 69(5). DOI:10.1111/aji.12065 · 3.32 Impact Factor
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    ABSTRACT: PROBLEM: Preterm premature rupture of fetal membranes (pPROM) occurs in 30-40% of spontaneous preterm births (PTB) and is associated with intra-amniotic infection and inflammation. The membranes may sense and respond to microbes via Toll-like receptors (TLRs); however, little is known about their expression and regulation in this tissue. The objective of this study was to evaluate the expression of TLRs 1-10 in fetal membranes after exposure to pathogens associated with intra-amniotic infection and PTB. METHOD OF STUDY: Normal human term fetal membrane explants were exposed to various bacteria. After 24 hrs, RNA was extracted and quantitative RT-PCR performed for TLRs1-10. RESULTS: Treatment of fetal membranes with Mycoplasma hominis increased expression of TLR4, TLR6, and TLR8 mRNA. Ureaplasma parvum upregulated TLR8 mRNA, and Porphyromonas gingivalis significantly increased fetal membrane TLR7 expression. In contrast, treatment with Gram-negative Escherichia coli (and its cell wall component lipopolysaccharide) downregulated TLR10 mRNA. No effect was detected for Ureaplasma urealyticum, Gardnerella vaginalis, or Group B Streptococcus. CONCLUSION: These findings demonstrate that different types of bacteria have distinct effects on fetal membrane TLR expression patterns. Moreover, these findings highlight the disparity of fetal membrane responses to infection and thus suggest heterogeneity in the mechanisms by which infection-associated pregnancy complications, such as pPROM and PTB, arise.
    American Journal Of Reproductive Immunology 09/2012; 69(1). DOI:10.1111/aji.12016 · 3.32 Impact Factor
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    ABSTRACT: STUDY QUESTION: What is the effect of pravastatin on antiphospholipid antibody (aPL) modulation of human first trimester trophoblast function? SUMMARY ANSWER: Pravastatin does not prevent the effects of aPL on human first trimester trophoblast cell function. WHAT IS KNOWN ALREADY: Antiphospholipid syndrome (APS) is associated with recurrent pregnancy loss and late pregnancy complications, such as pre-eclampsia, owing to direct targeting of the placenta by aPL. While treatment with heparin reduces the rate of pregnancy loss, the risk for severe pre-eclampsia remains high. Thus, there is a need to find alternative treatments for the prenatal management of patients with APS. Statins have recently been shown to prevent aPL-mediated fetal loss in mice but their effects on a human pregnancy model of APS have not yet been studied. DESIGN, DATA COLLECTION, METHODS: The human first trimester trophoblast cell line, HTR8, and human first trimester trophoblast primary cultures were incubated with or without a mouse anti-human beta 2 glycoprotein I (β(2)GPI) monoclonal antibody in the presence or absence of pravastatin. Cytokine and angiogenic factor secretion were measured by enzyme-linked immunosorbent assay and multiplex analysis. Cell migration was measured using a colorimetric two-chamber migration assay. MAIN FINDINGS: Using the human first trimester trophoblast cell line, HTR8, pravastatin significantly augmented, compared with no treatment, aPL-dependent secretion of interleukin (IL)-8 (P< 0.05), IL-1β (P< 0.05) and soluble endoglin (P< 0.01) but had no effect on aPL-induced up-regulation of vascular endothelial growth factor, placenta growth factor or growth-related oncogene alpha secretion. Furthermore, pravastatin alone limited basal HTR8 cell migration (P< 0.01), and did not mitigate the adverse effect of aPL on trophoblast migration. Pravastatin also had no impact on the secretion of pro-inflammatory cytokines and angiogenic factors by primary human first trimester trophoblast cells exposed to aPL. LIMITATIONS AND WIDER IMPLICATIONS OF THE FINDINGS: While our in vitro findings suggest that pravastatin may not be effective in preventing pregnancy complications in patients with APS, the in vivo condition may be more complex, and thus, more studies are needed to determine the effectiveness of pravastatin in the prevention of aPL-associated pregnancy complications in humans. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the American Heart Association.
    Human Reproduction 08/2012; 27(10):2933-40. DOI:10.1093/humrep/des288 · 4.59 Impact Factor

Publication Stats

3k Citations
352.78 Total Impact Points

Institutions

  • 2004–2014
    • Yale-New Haven Hospital
      • • Department of Laboratory Medicine
      • • Department of Pathology
      New Haven, Connecticut, United States
    • Wayne State University
      • Department of Obstetrics and Gynecology
      Detroit, Michigan, United States
  • 1970–2014
    • Yale University
      • • Department of Obstetrics, Gynecology and Reproductive Sciences
      • • School of Medicine
      New Haven, Connecticut, United States
  • 2012
    • The University of Manchester
      • Mental Health Research Group
      Manchester, England, United Kingdom
  • 2006
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2003–2004
    • Geisel School of Medicine at Dartmouth
      • Department of Microbiology and Immunology
      Hanover, New Hampshire, United States