Mesiano S, Mellon S H, Jaffe R B
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco 94143.
J Clin Endocrinol Metab. 1993 Apr;76(4):968-76. doi: 10.1210/jcem.76.4.8473412.
Polypeptide growth factors may play an important role in the regulation of human fetal adrenal cortical growth by mediating the tropic actions of ACTH. The abundance of mRNA encoding insulin-like growth factor-II (IGF-II) is high in the human fetal adrenal gland and is stimulated by ACTH in cultured fetal adrenal cortical cells. Therefore, we studied the mitogenic action, regulation, and localization of IGF-II and a closely related peptide, IGF-I, in primary cultures of human fetal adrenal cortical cells and whole human fetal adrenal glands. Recombinant human IGF-I and IGF-II stimulated proliferation of fetal adrenal cortical cells in a dose-dependent fashion (1-1000 ng/mL; 0.133-133 nM). At 1000 ng/mL (133 nM), both peptides increased cell number 1.8- to 2-fold. Combinations of IGF-I or -II (100 ng/mL; 13.3 nM) with basic fibroblast growth factor (bFGF; 0.1 ng/mL; 6 pM) or epidermal growth factor (EGF; 1.0 ng/mL; 0.17 nM) had a greater effect on proliferation than bFGF, EGF, or either of the IGFs alone, suggesting an additive interaction. IGF-II mRNA was detected in cultured adrenal cortical cells by in situ hybridization analysis, and its abundance was stimulated by ACTH. In contrast, IGF-I mRNA was not detected in cultured fetal zone cells and was not regulated by ACTH. In whole human fetal adrenal glands, IGF-II mRNA was detected in the definitive and fetal zones and in the capsule, whereas IGF-I mRNA was detected only in the capsule and not in the two cortical zones. Using Northern blot analysis, we found that mRNA encoding IGF-II was present in high abundance in fetal adrenal glands (16-22 weeks) and barely detectable in adult adrenals, whereas mRNA encoding IGF-I was present in very low abundance in the fetal adrenal, but was high in adult human adrenals. As IGF-II expression is high in the human fetal adrenal cortex and is regulated by ACTH, we propose that it is the dominant of the two IGFs regulating human fetal adrenal growth. The cooperative mitogenic effect of IGF-II with bFGF and EGF and the regulation of its expression by ACTH support the hypothesis that IGF-II may act as a mediator, in concert with bFGF and possibly EGF, of the tropic action of ACTH in regulating the rapid growth of the human fetal adrenal cortex during midgestation.
多肽生长因子可能通过介导促肾上腺皮质激素（ACTH）的促生长作用，在人类胎儿肾上腺皮质生长的调节中发挥重要作用。编码胰岛素样生长因子-II（IGF-II）的mRNA在人类胎儿肾上腺中含量很高，并在培养的胎儿肾上腺皮质细胞中受到ACTH的刺激。因此，我们研究了IGF-II和一种密切相关的肽IGF-I在人类胎儿肾上腺皮质细胞原代培养物和整个人类胎儿肾上腺中的促有丝分裂作用、调节和定位。重组人IGF-I和IGF-II以剂量依赖的方式刺激胎儿肾上腺皮质细胞增殖（1-1000 ng/mL；0.133-133 nM）。在1000 ng/mL（133 nM）时，两种肽均使细胞数量增加1.8至2倍。IGF-I或-II（100 ng/mL；13.3 nM）与碱性成纤维细胞生长因子（bFGF；0.1 ng/mL；6 pM）或表皮生长因子（EGF；1.0 ng/mL；0.17 nM）联合使用对增殖的影响比bFGF、EGF或单独的任何一种IGF更大，提示存在相加作用。通过原位杂交分析在培养的肾上腺皮质细胞中检测到IGF-II mRNA，其丰度受到ACTH的刺激。相反，在培养的胎儿带细胞中未检测到IGF-I mRNA，且其不受ACTH调节。在整个人类胎儿肾上腺中，在永久区、胎儿区和被膜中检测到IGF-II mRNA，而IGF-I mRNA仅在被膜中检测到，在两个皮质区未检测到。使用Northern印迹分析，我们发现编码IGF-II的mRNA在胎儿肾上腺（16-22周）中大量存在，在成人肾上腺中几乎检测不到，而编码IGF-I的mRNA在胎儿肾上腺中的丰度非常低，但在成人人类肾上腺中含量很高。由于IGF-II在人类胎儿肾上腺皮质中表达高且受ACTH调节，我们提出它是调节人类胎儿肾上腺生长的两种IGF中的主要因子。IGF-II与bFGF和EGF的协同促有丝分裂作用及其表达受ACTH调节支持了这样的假说，即IGF-II可能与bFGF以及可能与EGF协同，作为ACTH在调节妊娠中期人类胎儿肾上腺皮质快速生长的促生长作用的介质。
