This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted 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 Irwin, J. C. Articles by Giudice, L. C. Search for Related Content PubMed PubMed Citation Articles by Irwin, J. C. Articles by Giudice, L. C.

Insulin-Like Growth Factor (IGF)-II Inhibition of Endometrial Stromal Cell Tissue Inhibitor of Metalloproteinase-3 and IGF-Binding Protein-1 Suggests Paracrine Interactions at the Decidua:Trophoblast Interface during Human Implantation¹

Division of Reproductive Endocrinology and Infertility, Center for Research on Women’s Health and Reproductive Medicine, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, California 94305-5317

Address all correspondence and requests for reprints to: Linda C. Giudice, Ph.D., M.D., Department of Gynecology and Obstetrics, East Pavilion HH 333, Stanford Medical Center, Stanford, California 94305-5317. E-mail: giudice{at}stanford.edu

In human pregnancy, insulin-like growth factor (IGF)-II messenger RNA (mRNA) is expressed at the maternal-fetal interface exclusively by the placental trophoblast. Highest levels are expressed by the invading extravillous trophoblasts, which also secrete matrix metalloproteinases as they degrade the decidual extracellular matrix. In contrast, the maternal decidua expresses high levels of IGF-binding protein (IGFBP)-1 and tissue inhibitors of matrix metalloproteinase (TIMPs), both of which inhibit trophoblast invasiveness in vitro. The present study investigated the hypothesis that IGF-II may serve as a paracrine modulator of maternal restraints on invasion, by examining its effects on TIMP-3 and IGFBP-1 expression by decidualized endometrial stromal cells. Human endometrial stromal cells were decidualized in vitro with progesterone (P), after which 0–130 nM IGF-II and IGF analogs were added. IGFBP-1 in conditioned medium was assayed by immunoradiometric assay. In addition, Northern analyses were conducted using a PCR-generated 421-bp complementary DNA (cDNA) fragment corresponding to nucleotides 132–553 of the human TIMP-3 cDNA, and a 934-bp EcoRI fragment of the human IGFBP-1 cDNA. TIMP-3 mRNA transcripts of 2.2, 2.5, and 4.4 kilobases were detected in decidualized stromal cells not treated with IGF-II, but not detected in nondecidualized stromal cells, consistent with its known induction upon decidualization and in response to P. In decidualized stromal cells, IGF-II and Des(1-6) IGF-II, an analog with reduced affinity for IGFBPs, caused a dose-dependent inhibition of TIMP-3 mRNA expression. Long R³ IGF-I, an IGF analog with minimal affinity for IGFBPs, also significantly inhibited (79 ± 0.3%) TIMP-3 mRNA expression in these cells at 6 nM. Decidualized stromal cells secreted IGFBP-1 and expressed a 1.5-kilobase IGFBP-1 transcript, which was not detected in nondecidualized cells, consistent with its known induction upon decidualization and in response to P. IGF-II caused a dose-dependent inhibition of IGFBP-1 mRNA expression and protein secretion in decidualized stromal cells when added in molar excess of endogenous IGFBP-1 levels, with virtually complete inhibition at higher concentrations of IGF-II (65 and 130 nM). By comparison, Long R³ IGF-I inhibited IGFBP-1 expression with a 50% effective dose of 0.2–0.4 nM. These data suggest that the invading trophoblast has the capacity, via IGF-II, to inhibit maternal restraints on trophoblast invasiveness by regulating decidual TIMP-3 and IGFBP-1.

This article has been cited by other articles:

				N. Tawadros, L.A. Salamonsen, E. Dimitriadis, and C. Chen Facilitation of decidualization by locally produced ghrelin in the human endometrium Mol. Hum. Reprod., July 1, 2007; 13(7): 483 - 489. [Abstract] [Full Text] [PDF]

				G. S. Daftary and H. S. Taylor Endocrine Regulation of HOX Genes Endocr. Rev., June 1, 2006; 27(4): 331 - 355. [Abstract] [Full Text] [PDF]

				A. Toyofuku, T. Hara, T. Taguchi, Y. Katsura, K. Ohama, and Y. Kudo Cyclic and characteristic expression of phosphorylated Akt in human endometrium and decidual cells in vivo and in vitro Hum. Reprod., May 1, 2006; 21(5): 1122 - 1128. [Abstract] [Full Text] [PDF]

				M D Ashworth, J W Ross, D R Stein, D T Allen, L J Spicer, and R D Geisert Endocrine disruption of uterine insulin-like growth factor expression in the pregnant gilt Reproduction, October 1, 2005; 130(4): 545 - 551. [Abstract] [Full Text] [PDF]

				A. Jasinska, V. Han, A. T. Fazleabas, and J. J. Kim Induction of Insulin-Like Growth Factor Binding Protein-1 Expression in Baboon Endometrial Stromal Cells by Cells of Trophoblast Origin Reproductive Sciences, September 1, 2004; 11(6): 399 - 405. [Abstract] [PDF]

				A. Thathiah, M. Brayman, N. Dharmaraj, J. J. Julian, E. L. Lagow, and D. D. Carson Tumor Necrosis Factor {alpha} Stimulates MUC1 Synthesis and Ectodomain Release in a Human Uterine Epithelial Cell Line Endocrinology, September 1, 2004; 145(9): 4192 - 4203. [Abstract] [Full Text] [PDF]

				A. De Luca, M. De Falco, V. Fedele, L. Cobellis, A. Mastrogiacomo, V. Laforgia, I. L. Tuduce, M. Campioni, D. Giraldi, M. G. Paggi, et al. The Serine Protease HtrA1 Is Upregulated in the Human Placenta During Pregnancy J. Histochem. Cytochem., July 1, 2004; 52(7): 885 - 892. [Abstract] [Full Text] [PDF]

				A. Thathiah, C. P. Blobel, and D. D. Carson Tumor Necrosis Factor-alpha Converting Enzyme/ADAM 17 Mediates MUC1 Shedding J. Biol. Chem., January 24, 2003; 278(5): 3386 - 3394. [Abstract] [Full Text] [PDF]

				S. M. Firth and R. C. Baxter Cellular Actions of the Insulin-Like Growth Factor Binding Proteins Endocr. Rev., December 1, 2002; 23(6): 824 - 854. [Abstract] [Full Text] [PDF]

				V. Tsatsaris, A. Tarrade, P. Merviel, J. M. Garel, N. Segond, A. Jullienne, and D. Evain-Brion Calcitonin Gene-Related Peptide (CGRP) and CGRP Receptor Expression at the Human Implantation Site J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4383 - 4390. [Abstract] [Full Text] [PDF]

				L. C. Giudice, C. A. Conover, L. Bale, G. H. Faessen, K. Ilg, I. Sun, B. Imani, L.-F. Suen, J. C. Irwin, M. Christiansen, et al. Identification and Regulation of the IGFBP-4 Protease and Its Physiological Inhibitor in Human Trophoblasts and Endometrial Stroma: Evidence for Paracrine Regulation of IGF-II Bioavailability in the Placental Bed during Human Implantation J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2359 - 2366. [Abstract] [Full Text] [PDF]