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Hum. Reprod. Advance Access published online on May 20, 2008
Human Reproduction, doi:10.1093/humrep/den121
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed: the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given: if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative word this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Leukemia inhibitory factor promotes human first trimester extravillous trophoblast adhesion to extracellular matrix and secretion of tissue inhibitor of metalloproteinases-1 and -2

Alejandro Tapia1, Lois A. Salamonsen1, Ursula Manuelpillai2 and Evdokia Dimitriadis1,3

1 Prince Henry's Institute of Medical Research, PO Box, 5152 Clayton, VIC 3168, Australia 2 Monash University Department of Obstetrics and Gynecology, Clayton, VIC 3168, Australia

3 Correspondence address. Tel +613-9594-4392; Fax: +613-9594-6125; E-mail: evdokia.dimitriadis{at}princehenrys.org

BACKGROUND: Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that is essential for blastocyst implantation in mice. It has been suggested that LIF may play a role in human first trimester extravillous trophoblast (EVT) invasion. The aim of the present study was to establish whether LIF induces changes in EVT function related to invasiveness.

METHODS: Primary first trimester human EVT cell cultures were treated with/without LIF and the effects on cell adhesion to fibronectin (FN), vitronectin (VN) and laminin (LN) were assessed. Transcript levels of integrin subunits that mediate cell adhesion to these extracellular matrix (ECM) elements were determined by real-time RT–PCR. Matrix metalloproteinase (MMP)2 and MMP9 secretion was assessed by gelatine zymography and tissue inhibitors matrix metalloproteinase (TIMP) -1 and TIMP-2 secretion by enzyme-linked immunosorbent assay.

RESULTS: EVT cells showed increased adhesion to FN, VN and LN ECM elements in response to LIF (20, 20 and 29%, respectively, P < 0.05 FN and VN compared to control; and P < 0.001 LN compared to control). Integrin β4 mRNA levels decreased by 50% following LIF treatment (P < 0.001 versus control). MMP2 and MMP9 secretion was not affected by LIF but LIF did increase secretion of TIMP-1 and -2 (P < 0.001 versus control). LIF stimulated the phosphorylation of signal transducer and activator of transcription (STAT) 3 protein while it did not affect STAT3 protein abundance. The addition of a LIF inhibitor attenuated the LIF-induced STAT3 phosphorylation in EVT.

CONCLUSION: The results suggest that LIF can regulate EVT invasion, suggesting an important role in early placental development.

Key words: leukemia inhibitory factor/extravillous trophoblasts/trophoblast invasion/cell adhesion/matrix metalloproteinases

Submitted on October 16, 2007; resubmitted on February 18, 2008; accepted on March 18, 2008.


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