Effects of insulin-like growth factor-I and Progranulin on a human trophoblast model.

Gestational diabetes and obesity are associated with increased placental weight and fetal birth weight. Placental development is mainly promoted by trophoblast proliferation and various humoral factors. Insulin-like growth factor-1 (IGF-I) levels are increased in mothers with gestational diabetes, and trophoblast proliferation is promoted in a dose-dependent manner. In addition, progranulin (PGRN), an adipokine involved in obesity, plays an important role in the proliferation of trophoblast cell lines. IGF-I and PGRN independently affect placental development, but there are many unknowns regarding their interaction. In this study, we investigated the combined effects of IGF-I and PGRN on trophoblast proliferation using the human choriocarcinoma cell line JEG-3. Cell proliferation was evaluated using a cell counting method and a water-soluble tetrazolium-1 assay. Furthermore, the effect of PGRN on the intracellular signaling pathways of IGF-I, particularly the phosphorylation of Akt and Erk1/2, was evaluated using western blotting. IGF-I significantly increased cell proliferation in JEG-3 cells. However, the proliferative effect of a low concentration of IGF-I (100 ng/mL) was inhibited by simultaneous treatment with PGRN. Pretreatment with PGRN significantly suppressed phosphorylation of Erk1 at a low concentration of IGF-I (P < 0.01) but had no effect on phosphorylation of Akt. PGRN may suppress IGF-I-induced trophoblast proliferation by regulating the phosphorylation of Erk1/2, especially at low concentrations of IGF-I. PGRN modulates the proliferative effects of IGF-I in a complex manner, dependent on the concentration and timing of exposure. These findings indicate that the placental growth factor IGF-I may be regulated by PGRN.