Antiphospholipid antibodies limit trophoblast migration by reducing IL-6 production and STAT3 activity.
OBJECTIVE
Women with antiphospholipid antibodies (aPL) are at risk of recurrent miscarriage and pre-eclampsia. aPL target the placenta by binding to beta(2)-glycoprotein I (beta(2) GPI) expressed by the trophoblast. The objective of this study was to evaluate if and how aPL affect first trimester trophoblast migration.


METHODS
First trimester trophoblast cells were treated with anti-beta(2) GPI monoclonal antibodies. Migration was determined using a two-chamber assay. Interleukin (IL)-6 production was evaluated by RT-PCR and enzyme-linked immunosorbent assay, and signal transducer and activator of transcription 3 (STAT3) activation was assessed by western blot.


RESULTS
Trophoblast cells constitutively secreted IL-6 in a time-dependent manner and this directly correlated with STAT3 phosphorylation. In the presence of anti-beta(2) GPI Abs, trophoblast IL-6 mRNA levels and secretion was downregulated in a Toll-like receptor 4/MyD88-independent manner and this correlated with a reduction in phosphorylated STAT3 levels. In addition, the anti-beta(2) GPI Abs reduced the migratory potential of trophoblast. Heparin was able to reverse aPL-dependent inhibition of trophoblast IL-6 secretion and migration.


CONCLUSIONS
This study demonstrates that aPL limit trophoblast cell migration by downregulating trophoblast IL-6 secretion and STAT3 activity. As heparin was unable to prevent these effects, our findings may explain why women with antiphospholipid syndrome, treated with heparin, remain at risk of developing obstetrical syndromes, associated with impaired deep placentation, such as pre-eclampsia.
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.
Melissa J
MJ
Mulla
Kledia
K
Myrtolli
Jan J
JJ
Brosens
Larry W
LW
Chamley
Joanne Y
JY
Kwak-Kim
Michael J
MJ
Paidas
Vikki M
VM
Abrahams
D017152:Antibodies, Antiphospholipid / Q000276:immunology*; D002465:Cell Movement; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014327:Trophoblasts / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D053482:beta 2-Glycoprotein I / Q000276:immunology
D017152:Antibodies, Antiphospholipid; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053482:beta 2-Glycoprotein I