胎児発育・成熟におけるIGF-Iとその結合蛋白の意義 : 特に脱落膜/胎盤局所の調節と発育・成熟に伴う細胞内代謝機構の発現への関与について (<シンポジウム>子宮内環境と胎児)

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Insulin-like growth factor-I (IGF-I) is one of growth factors that circulates bound to specific, high affinity binding proteins (IGFBPs). Physiological significance of IGF-I and IGFBPs on fetal growth is investigated in this study. In mother, circulating levels of IGF-I are increased during pregnancy in which placental hormones take the place of pituitary GH to regulate IGF-I during pregnancy and correlates with fetal birth weight. IGFBPs except IGFBP-1 in the maternal circulation are markedly reduced compared to those of non pregnant women due to increased activity of protease(s) while IGFBP-1 gradually increased throughout pregnancy and negatively correlates with fetal weight. IGF-I stimulated ^3H-AIB uptake and release by cultured trophoblast cells in a dose dependent manner. Furthermore, fetal growth and the transfer of ^3H-AIB to fetus is inhibited when IGF-I is neutralized by polyclonal antibody. These results indicate that maternal IGF-I stimulates fetal growth by activating placental transport of nutrients to fetus. In contrast, IGFBP-1 inhibits both ^<125>I-IGF-I binding to placental membrane and ^3H-glycine uptake of trophoblast cells by IGF-I in a dose dependent manner. Moreover, fetal growth and the transfer of ^3H-AIB to fetus are accelerated when IGFBP-1 is neutralized by polyclonal antibody, suggesting that maternal IGFBP-1 inhibits fetal growth by inhibiting IGF-I action on the placenta. IGF-I and four IGFBPs including IGFBP-1, -2, -3, and -4 are localized in cytotrophoblast of term placenta. Similarly IGFBP-1, -2, and -4 are detected in medium conditioned by term decidua cells by Western ligand blot in which release of IGFBP-1 and -4 are diminished by IGF-I and all three IGFBPs are increased by progesterone. Thus, there is a complicated autocrine/paracrine regulation between decidua and placenta and IGF-I action on fetal growth is presumed to be modified by this local regulation. Fetallevels of IGF-I and IGFBP-1 are positively and negatively correlate with fetal weight, respectively. The isomers of phosphorylated IGFBP-1 in cord sera are separated by anion ion exchange chromatography in which one nonphosphorylated and four phosphorylated IGFBP-1 are detected. In pared blood samples from mid-term delivery, percentage of nonphosphorylated IGFBP-1 is higher in fetal blood compared to those in mother. Similarly, percentage of nonphosphorylated IGFBP-1 is elevated in AFD infants than is SFD infants from term delivery. Thus, the proportion of nonphosphorylated and phosphorylated isomers of IGFBP-1 varies corresponding to fetal growth. Nonphosphorylated IGFBP-1 enhances IGF-I-mediated ^3H-AIB uptake by cultured fibroblast cells while phosphorylated IGFBP-1 inhibits when cells are incubated with IGF-I under the presence of these isoforms of IGFBP-1. Affinity crosslinking experiments demonstrates that down regulation of receptors for IGF-I is prevented when incubate cells with IGF-I under the presence of nonphosphorylated IGFBP-1 while cell surface receptors are markedly reduced by down regulation of receptors when cells are incubated with IGF-I alone or with phosphorylated IGFBP-1. Furthermore, IGF-I-induced desensitization of these cells in terms of ^3H-AIB uptake is inhibited when cells are incubated with IGF-I in the presence of nonphosphorylated IGFBP-1. Thus, the mechanism by which nonphosphorylated IGFBP-1 potentiates IGF-I action is elucidated and this mechanism may be a reasonable explanation for remarkable fetal growth. Number and volume of lamellar bodies in lung of fetal mice increased when IGFBP-1 is neutralized while lung maturity is inhibited after neutralization of IGF-I suggesting that fetal IGF-I and IGFBP-1 are involved in not only fetal growth but also in maturation. IGF-I is only one of many factors that influences fetal growth, however, it is notable that this growth factor is directly involved in fetal growth and maturation by modifying feto-maternal interaction.
1994-08-01

胎児発育・成熟におけるIGF-Iとその結合蛋白の意義 : 特に脱落膜/胎盤局所の調節と発育・成熟に伴う細胞内代謝機構の発現への関与について (<シンポジウム>子宮内環境と胎児)

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