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This version published online on May 13, 2004
Endocrinology, doi:10.1210/en.2004-0383
A more recent version of this article appeared on August 1, 2004
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Submitted on March 25, 2004
Accepted on May 4, 2004

LEPTIN INDUCED INCREASE IN LEUKEMIA INHIBITORY FACTOR AND ITS RECEPTOR BY HUMAN ENDOMETRIUM IS PARTIALLY MEDIATED BY INTERLEUKIN 1 RECEPTOR SIGNALING

R. R. Gonzalez*, B. R. Rueda, M. P. Ramos, R. D. Littell, S. Glasser, and P. C. Leavis

Boston Biomedical Research Institute (BBRI), 64 Grove St., Watertown, MA 02472; Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA 02114; Harvard Medical School, Boston, MA 02115; Dept. of Molecular and Cellular Biology, Baylor College of Medicine, TX 77030; Dept of Physiology, Tufts University School of Medicine, Boston, MA 02111

* To whom correspondence should be addressed. E-mail: gonzalezr{at}bbri.org.

Leptin and leukemia inhibitory factor (LIF) have been implicated as important mediators of implantation. The present study was designed to investigate whether leptin can directly regulate the expression of LIF and its receptor (LIF-R) in human endometrial cells and/or whether leptin-induced effects are linked to, or regulated in part by interleukin-1 (IL-1) signaling. Primary endometrial cells and endometrial epithelial cell lines (HES and Ishikawa cells) were cultured for 24-48 h in a medium containing insulin (5 µg/ml) and leptin (3, 10 and 62 nM) or IL-1{beta} (0.6, 3 and 10 nM) in the presence or absence of cytokines and/or receptor antagonists. The endpoints included phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the relative levels of LIF, LIF-R, IL-1{beta}, IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type I (IL-1R tI) as determined by ELISA or Western blotting techniques. Leptin treatment increases the level of phosphorylated STAT3 (p-STAT3), LIF-R and LIF. Leptin also increases the levels of IL-1 ligand, receptor and antagonist as was previously reported. Blockade of OB-R with antibodies or with a specific OB-R inhibitor (LPA-2) abrogated leptin-induced effects suggesting that leptin binding to its receptor activates Janus kinase 2 (JAK2)/STAT3 signaling. Treatment of endometrial cells with IL-1{beta} also results in elevated levels of LIF-R. Interestingly, the inhibition of IL-1R tI with a specific antibody or with IL-1Ra negatively affects both leptin-induced and IL-1-induced effects on LIF-R levels. Abnormal endometrial LIF expression has been associated with human infertility and leptin has profound effects on the levels of LIF, IL-1 and their cognate receptors in vitro. Thus, it is tempting to speculate that leptin's role in vivo could include the regulation of other key cytokines to be fundamental to endometrial receptivity during implantation (i.e. LIF and IL-1).
Key words: Leptin • leukemia inhibitory factor • endometrium • implantation • interleukin-1




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