drenomedullin 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 cytotro-
phoblast 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.