This Article Full Text Full Text (PDF) All Versions of this Article: 145/8/3850    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gonzalez, R. R. Articles by Leavis, P. C. Search for Related Content PubMed PubMed Citation Articles by Gonzalez, R. R. Articles by Leavis, P. C.

Leptin-Induced Increase in Leukemia Inhibitory Factor and Its Receptor by Human Endometrium Is Partially Mediated by Interleukin 1 Receptor Signaling

Boston Biomedical Research Institute (R.R.G., M.P.R., P.C.L.), Watertown, Massachusetts 02472; Vincent Center for Reproductive Biology (R.R.G., B.R.R., M.P.R., R.D.L.), Massachusetts General Hospital, Boston, Massachusetts 02114; Harvard Medical School (B.R.R., R.D.L.), Boston, Massachusetts 02115; Department of Molecular and Cellular Biology (S.G.), Baylor College of Medicine, Texas 77030; and Department of Physiology (P.C.L.), Tufts University School of Medicine, Boston, Massachusetts 02111

Address all correspondence and requests for reprints to: R. R. Gonzalez, Boston Biomedical Research Institute, 64 Grove Street, Watertown, Massachusetts 02472. 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 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-1ß (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-1ß, 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, 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 (leptin peptide antagonist-2) abrogated leptin-induced effects, suggesting that leptin binding to its receptor activates Janus kinase 2/STAT3 signaling. Treatment of endometrial cells with IL-1ß 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).

This article has been cited by other articles:

				A.A Fouladi-Nashta, L Mohamet, J.K Heath, and S.J Kimber Interleukin 1 Signaling Is Regulated by Leukemia Inhibitory Factor (LIF) and Is Aberrant in Lif-/- Mouse Uterus Biol Reprod, July 1, 2008; 79(1): 142 - 153. [Abstract] [Full Text] [PDF]

				A. K. Styer, B. T. Sullivan, M. Puder, D. Arsenault, J. C. Petrozza, T. Serikawa, S. Chang, T. Hasan, R. R. Gonzalez, and B. R. Rueda Ablation of Leptin Signaling Disrupts the Establishment, Development, and Maintenance of Endometriosis-Like Lesions in a Murine Model Endocrinology, February 1, 2008; 149(2): 506 - 514. [Abstract] [Full Text] [PDF]

				R. R. Gonzalez, S. Cherfils, M. Escobar, J. H. Yoo, C. Carino, A. K. Styer, B. T. Sullivan, H. Sakamoto, A. Olawaiye, T. Serikawa, et al. Leptin Signaling Promotes the Growth of Mammary Tumors and Increases the Expression of Vascular Endothelial Growth Factor (VEGF) and Its Receptor Type Two (VEGF-R2) J. Biol. Chem., September 8, 2006; 281(36): 26320 - 26328. [Abstract] [Full Text] [PDF]

				S. J Kimber Leukaemia inhibitory factor in implantation and uterine biology Reproduction, August 1, 2005; 130(2): 131 - 145. [Abstract] [Full Text] [PDF]

				M. P. Ramos, B. R. Rueda, P. C. Leavis, and R. R. Gonzalez Leptin Serves as an Upstream Activator of an Obligatory Signaling Cascade in the Embryo-Implantation Process Endocrinology, February 1, 2005; 146(2): 694 - 701. [Abstract] [Full Text] [PDF]