Adrenomedullin 2/Intermedin Regulates HLA-G in Human Trophoblasts
Adrenomedullin 2/Intermedin Regulates HLA-G in Human Trophoblasts
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DOI：
10.1095/biolreprod.110.086835
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发表时间：
2011-12-01
影响因子：
3.6
通讯作者：
Yallampalli, Chandra
中科院分区：
文献类型：
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作者：
Chauhan, Madhu;Balakrishnan, Meena;Yallampalli, Chandra
肾上腺髓质素 2 (ADM2)，也称为 intermedin (IMD)，在人胎盘的滋养层细胞中表达，增强妊娠早期 HTR-8SV/neo 细胞的侵袭和迁移。在妊娠大鼠中进一步输注 ADM2 拮抗剂会导致胎儿胎盘生长受限，表明 ADM2 在维持成功妊娠中发挥作用。本研究旨在评估 ADM2 蛋白是否存在于蜕膜组织中并与 HLA-G 阳性细胞滋养层细胞和自然杀伤细胞共定位；评估 ADM2 是否调节滋养层细胞中 HLA-G 的表达；并鉴定丝裂原激活蛋白激酶（MAPK）信号通路是否参与ADM2诱导的滋养层细胞侵袭和迁移。利用免疫组织化学方法和 RT-PCR，本研究表明 ADM2 蛋白与人类妊娠早期蜕膜组织中表达 HLA-G 的细胞滋养层细胞以及 NCAM1 (CD56) 免疫反应性共定位，并且 ADM2 mRNA 在外周血自然杀伤细胞中表达。此外，ADM2剂量依赖性地增加HTR-8SV/neo细胞以及足月胎盘绒毛外植体中HLA-G抗原的表达，表明ADM2参与滋养层细胞中HLA-G的调节。此外，RAF 和 MAPK3/1 的抑制剂 manumycin 和 U0126 分别干扰 RAF 和 MAPK3/1 的活性，可减少 ADM2 诱导的 HTR-8SV/neo 细胞侵袭和迁移。总之，本研究表明 ADM2 可能参与调节人类妊娠母胎界面的 HLA-G 抗原，并通过 MAPK3/1 磷酸化促进滋养层侵袭和迁移。
Adrenomedullin 2 (ADM2), also referred to as intermedin (IMD), is expressed in trophoblast cells in human placenta and enhances the invasion and migration of first-trimester HTR-8SV/neo cells. Further infusion of ADM2 antagonist in pregnant rat causes fetoplacental growth restriction, suggesting a role for ADM2 in maintaining a successful pregnancy. This study was undertaken to assess whether ADM2 protein is present in decidual tissue and colocalized with HLA-G-positive cytotrophoblast cells and natural killer cells; to assess whether ADM2 regulates expression of HLA-G in trophoblast cells; and to identify whether mitogen-activated protein kinase (MAPK) signaling pathway is involved in ADM2-induced trophoblast cell invasion and migration. Using immunohistochemical methods and RT-PCR, this study shows that ADM2 protein is colocalized with HLA-G-expressing cytotrophoblast cells as well as with NCAM1 (CD56) immunoreactivity in human first-trimester decidual tissue, and that ADM2 mRNA is expressed in peripheral blood natural killer cells. Further, ADM2 dose dependently increases the expression of HLA-G antigen in HTR-8SV/neo cells as well as in term placental villi explants, suggesting involvement of ADM2 in the regulation of HLA-G in trophoblast cells. In addition, interference with the activity of RAF and MAPK3/1 by their inhibitors, manumycin and U0126, respectively, reduces ADM2-induced HTR-8SV/neo cell invasion and migration. In summary, this study suggests a potential involvement for ADM2 in regulating HLA-G antigen at the maternal-fetal interface in human pregnancy and facilitating trophoblast invasion and migration via MAPK3/1 phosphorylation.