title: Adrenomedullin 2/intermedin regulates HLA-G in human trophoblasts.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555-1062, USA. mschauha@utmb.edu
authors.forename: Madhu
authors.initials: M
authors.lastname: Chauhan
authors.forename: Meena
authors.initials: M
authors.lastname: Balakrishnan
authors.forename: Uma
authors.initials: U
authors.lastname: Yallampalli
authors.forename: Janice
authors.initials: J
authors.lastname: Endsley
authors.forename: Gary D V
authors.initials: GD
authors.lastname: Hankins
authors.forename: Regan
authors.initials: R
authors.lastname: Theiler
authors.forename: Chandra
authors.initials: C
authors.lastname: Yallampalli
mesh_terms: D019898:Autocrine Communication; D002460:Cell Line; D002465:Cell Movement; D004789:Enzyme Activation; D005260:Female; D059951:HLA-G Antigens / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019899:Paracrine Communication; D036361:Peptide Hormones / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: C484330:ADM2 protein, human; D059951:HLA-G Antigens; D036361:Peptide Hormones; D012333:RNA, Messenger; D019908:Proto-Oncogene Proteins c-raf