Insulin-like growth factor (IGF)-II inhibition of endometrial stromal celltissue inhibitor of metalloproteinase-3 and IGF-binding protein-1 suggestsparacrine interactions at the decidua : trophoblast interface during humanimplantation

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 tro phoblasts, 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 matr ix metalloproteinase (TIMPs), both of which inhibit trophoblast invasivenes s in vitro. The present study investigated the hypothesis that IGF-II may s erve as a paracrine modulator of maternal restraints on invasion, by examin ing its effects on TIMP-3 and IGFBP-1 expression by decidualized endometria l stromal cells. Human endometrial stromal cells were decidualized in vitro with progesterone (P), after which 0-130 nM IGF-II and IGF analogs were ad ded. 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 t he 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 d ecidualized stromal cells not treated with IGF-II, but not detected in nond ecidualized stromal cells, consistent with its known induction upon decidua lization and in response to P. In decidualized stromal cells, IGF-II and De s(1-6) IGF-II an analog with reduced affinity for IGFBPs, caused a dose-dep endent inhibition of TIMP-3 mRNA expression. Long R-3 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 wa s not detected in nondecidualized cells, consistent with its known inductio n upon decidualization and in response to P. IGF-II caused a dose-dependent inhibition of ICFBP-1 mRNA expression and protein secretion in decidualize d stromal cells when added in molar excess of endogenous ICFBP-1 levels, wi th virtually complete inhibition at higher concentrations of IGF-II (65 and 130 nM).