The role of leukemia inhibitory factor in tubal ectopic pregnancy.
BACKGROUND
Ectopic pregnancy is unique to humans and a leading cause of maternal morbidity and mortality. The etiology remains unknown however factors regulating embryo implantation likely contribute. Leukemia inhibitory factor (LIF) has roles in extravillous trophoblast adhesion and invasion and is present in ectopic implantation sites. We hypothesised that LIF facilitates blastocyst adhesion/invasion in the Fallopian tube, contributing to ectopic pregnancy.


METHODS
We immunolocalised LIF receptor (R) in tubal ectopic pregnancy (N = 5). We used an oviduct cell line (OE-E6/E7) to model Fallopian tube epithelial cells and a trophoblast spheroid co-culture model (HTR-8/SVneo cell line formed spheroids) to model blastocyst attachment to the Fallopian tube. We examined LIF signaling pathways in OE-E6/E7 cells by Western blot. The effect of LIF and LIF inhibition (using a novel LIF inhibitor, PEGLA) on first-trimester placental outgrowth was determined.


RESULTS
LIFR localised to villous and extravillous trophoblast and Fallopian tube epithelium in ectopic pregnancy. LIF activated STAT3 but not the ERK pathway in OE-E6/E7 cells. LIF stimulated HTR-8/SVneo spheroid adhesion to OE-E6/E7 cells which was significantly reduced after PEGLA treatment. LIF promoted placental explants outgrowth, while co-treatment with PEGLA blocked outgrowth.


CONCLUSIONS
Our data suggests LIF facilitates the development of ectopic pregnancy by stimulating blastocyst adhesion and trophoblast outgrowth from placental explants. Ectopic pregnancy is usually diagnosed after 6 weeks of pregnancy, therefore PEGLA may be useful in targeting trophoblast growth/invasion.


CONCLUSIONS
LIF may contribute to the development of ectopic pregnancies and that pharmacologically targeting LIF-mediated trophoblast outgrowth may be useful as a treatment for ectopic pregnancy.
Prince Henry's Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia; Faculty of Medicine, Nursing & Health Sciences, Wellington Road, Monash University, Clayton, Victoria 3800, Australia.
T
T
Krishnan
A
A
Winship
S
S
Sonderegger
E
E
Menkhorst
A W
AW
Horne
J
J
Brown
J-G
JG
Zhang
N A
NA
Nicola
S
S
Tong
E
E
Dimitriadis
D000293:Adolescent; D000328:Adult; D001755:Blastocyst / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D010064:Embryo Implantation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005187:Fallopian Tubes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D005260:Female; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010920:Placenta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011092:Polyethylene Glycols / Q000494:pharmacology; D011247:Pregnancy; D011274:Pregnancy, Tubal / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D050796:STAT3 Transcription Factor / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D046509:Tissue Culture Techniques; D055815:Young Adult
C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C525879:pegylated MH35-BD-Q29A+G124R protein; D011092:Polyethylene Glycols
EVT; Ectopic; Implantation; Leukemia inhibitory factor; Placenta; Pregnancy