Binding proteins for the insulin-like growth factors: structure, regulation and function

The comparison of the immunological state of pregnancy to an immunosuppressed host-graft model continues to lead research and clinical practice to ill-defined approaches. This Review discusses recent evidence that supports the idea that immunological responses at the receptive maternal-fetal interface are not simply suppressed but are instead highly dynamic. We discuss the crucial role of trophoblast cells in shaping not only the way in which immune cells respond to the invading blastocyst but also how they collectively react to external stimuli. We also discuss the role of the microbiota in promoting a tolerogenic maternal immune system and highlight how subclinical viral infections can disrupt this status quo, leading to pregnancy complications.

The unique immunological and microbial aspects of pregnancy

The placenta expresses genes for insulin-like growth factors (IGFs) and possesses IGF-receptors, suggesting that placental growth is regulated by IGFs in an autocrine manner. We have previously shown that human decidua, but not placenta, synthesizes and secretes a 34 K IGF-binding protein (34 K IGF-BP) called placental protein 12. We now used human choriocarcinoma JEG-3 cell monolayer cultures and recombinant (Thr59)IGF-I as a model to study whether the decidual 34 K IGF-BP is able to modulate the receptor binding and biological activity of IGFs in trophoblasts. JEG-3 cells, which possess type I IGF receptors, were unable to produce IGF-BPs. Purified 34 K IGF-BP specifically bound [125I]iodo-(Thr59)IGF-I. Multiplication-stimulating activity had 2.5% the potency of (Thr59)IGF-I, and insulin had no effect on the binding of [125I] iodo-(Thr59)IGF-I. 34 K IGF-BP inhibited the binding of [125I] iodo-(Thr59)IGF-I to JEG-3 monolayers in a concentration-dependent manner by forming with the tracer a soluble complex that could not bind to the cell surface as demonstrated by competitive binding and cross-linking experiments. After incubating the cell monolayers with [125I]iodo-(Thr59)IGF-I in the presence of purified binding protein, followed by cross-linking, no affinity labeled bands were seen on autoradiography. In contrast, an intensely labeled band at 40 K was detected when the incubation medium was analyzed, suggesting that (Thr59)IGF-I and 34 K IGF-BP formed a complex in a 1:1 molar ratio. Also, 34 K IGF-BP inhibited both basal and IGF-I-stimulated uptake of alpha-[3H]aminoisobutyric acid in JEG-3 cells. RNA analysis revealed that IGF-II is expressed in JEG-3 cells. We conclude that decidual 34 K IGF-BP inhibits the cellular binding and biological action of IGFs in JEG-3 cells. Our data show that JEG-3 cells represent a cell type that can produce IGF, but not IGF-BPs. These cells may thus provide a useful model system for a better understanding of autocrine growth regulation mediated by the IGFs.

Insulin-like growth factor (IGF) binding protein from human decidua inhibits the binding and biological action of IGF-I in cultured choriocarcinoma cells.

Cloning, characterization, and expression of a human insulin-like growth factor binding protein.

Publisher Summary This chapter provides an overview of insulin-like growth factor-binding proteins (IGF-BP). The insulin-like growth factors (IGFs)—or somatomedins—constitute a family of growth hormone (GH)-dependent peptides with both anabolic and mitogenic activities for a wide variety of tissues and cell lines. IGF-I and -II are characterized by a striking structural homology with human proinsulin. The human gene for IGF-II is located on the short arm of chromosome 11 in close proximity to the gene for insulin and spans over 30 kb of DNA. This gene is composed of at least eight exons. The preprohormone consists of a 24-amino-acid signal peptide, a 67-amino-acid mature peptide, and a carboxy-terminal peptide of 89 amino acids. Significant diversity exists in the 5'-untranslated regions, where different mRNA species arise as a result of distinct promoters and alternative RNA splicing. Both IGF-I and -II are synthesized in a wide variety of tissues. The close relationship between insulin and IGF-I receptors is not surprising, given the binding affinities and structural similarities of the two receptors. Unlike the insulin and IGF-I receptors, the type 2 IGF receptor is characterized by a long extracellular domain, containing 15 repeat sequences of approximately 150 residues, a 23-residue transmembrane domain, and a small 164-residue cytoplasmic domain. No homology exists between the type 2 IGF receptor and the insulin or type 1 receptor. The initial characterization of IGF-BPs was done by gel filtration chromatography. The chapter discusses radioreceptor assays, affinity labeling, western ligand blotting, and immune-precipitation among other methods of detection.

Insulinlike growth factor-binding proteins.

Alpha interferon in human pregnancy

The synthesis and secretion of placental protein 12 (PP12) by early pregnancy decidua and trophoblast were studied in vitro from tissues obtained by curettage during elective termination of pregnancy (weeks 8–14). The tissue explarits were incubated in Ham’s F–10 medium for a 27–h period, and the PP12 levels in media and tissue homogenates were measured by RIA. De nouo synthesis of PP12 was assessed by measuring the incorporation of radioactivity into PP12 after 20 h of incubation of tissues with 20⁄iCi⁄ml [35S]methionine. PP12 from the culture medium wasimmunoprecipitated with anti–PPl2(A) antiserum, and the immunoprecipitate was analyzed by sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The initial tissue content of PP12 was 10–to 72–fold higher in decidua than in trophoblast. The total amount of radioimmunoassayable PP12 released into medium by decidual explants during the 27–h incubation period together with that present in the tissues at the end of incubation exceeded the initial tissue c...

Synthesis of placental protein 12 by decidua from early pregnancy.

Identification of high-risk pregnancy by the routine measurement of pregnancy-specific β1-glycoprotein

Summary: A prospective survey of 2,069 women delivered during 1976 and 1977 at St. Bartholomew's Hospital was undertaken to evaluate a variety of clinical, ultrasonic and biochemical variables in the prediction of unsatisfactory fetal outcome. Severe pre-eclampsia and depressed maternal serum levels of human placental lactogen were each associated with a high fetal risk.

M. Menabawey

Papers

Alpha interferon in human pregnancy

Synthesis of placental protein 12 by decidua from early pregnancy.

Identification of high-risk pregnancy by the routine measurement of pregnancy-specific β1-glycoprotein

Is Placental Function Testing Worthwhile? An Update on Placental Lactogen

The relation between the concentration of placental specific proteins in retroplacental and peripheral blood