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Antiphospholipid Antibodies Induce a Pro-Inflammatory Response in First Trimester Trophoblast Via the TLR4/MyD88 Pathway

Mulla, MJ; Brosens, JJ; Chamley, LW; Giles, I; Pericleous, C; Rahman, A; Joyce, SK; ... Abrahams, VM; + view all (2009) Antiphospholipid Antibodies Induce a Pro-Inflammatory Response in First Trimester Trophoblast Via the TLR4/MyD88 Pathway. AM J REPROD IMMUNOL , 62 (2) 96 - 111. 10.1111/j.1600-0897.2009.00717.x.

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Abstract

ProblemWomen with antiphospholipid antibodies (aPL) are at risk for recurrent miscarriage, pre-eclampsia, and pre-term labor. aPL target the placenta directly by binding to beta(2)-glycoprotein I (beta(2)GPI) expressed on the surface of trophoblast cells. The objective of this study was to determine the effects of aPL on trophoblast function and the mechanisms involved.Method of studyFirst trimester trophoblast cells were treated with anti-beta(2)GPI monoclonal antibodies and patient-derived aPL, after which cell survival and function was evaluated.ResultsWe report that anti-beta(2)GPI antibodies trigger an inflammatory response in trophoblast, characterized by increased secretion of interleukin (IL)-8, MCP-1, GRO-alpha, and IL-1 beta, and that this occurs in a TLR-4/MyD88-dependent manner. At high concentrations, these antibodies also induce caspase-mediated cell death. This was attenuated upon disabling of the MyD88 pathway, suggesting that anti-beta(2)GPI-induced inflammatory mediators compromise trophoblast survival by acting in an autocrine/paracrine manner. Enhanced IL-8, GRO-alpha, and IL-1 beta secretion also occurred when trophoblast cells were incubated with antibodies from patients with antiphospholipid syndrome. Heparin, which acts as a pro-survival factor in human trophoblast, attenuated the anti-beta(2)GPI antibody-mediated cell death, and also the pro-inflammatory response, but only at high concentrations.ConclusionThese findings demonstrate that aPL triggers a placental inflammatory response via the TLR-4/MyD88 pathway, which in turn compromises trophoblast survival. Thus, the TLR-4/MyD88 pathway may provide a new therapeutic target to improve pregnancy outcome in antiphospholipid syndrome patients.

Type: Article
Title: Antiphospholipid Antibodies Induce a Pro-Inflammatory Response in First Trimester Trophoblast Via the TLR4/MyD88 Pathway
DOI: 10.1111/j.1600-0897.2009.00717.x
Keywords: Apoptosis, autoantibodies, human, inflammation, toll-like receptor, SYSTEMIC-LUPUS-ERYTHEMATOSUS, IN-VITRO, PREGNANCY FAILURE, BETA(2)-GLYCOPROTEIN I, RECURRENT MISCARRIAGE, HUMAN PLACENTA, TISSUE FACTOR, FETAL INJURY, NAIVE MICE, HEPARIN
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/1321782
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