Hum. Reprod. Advance Access originally published online on December 16, 2008
Human Reproduction 2009 24(3):553-561; doi:10.1093/humrep/den408
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Localization of matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitors for MMPs (TIMPs) in uterine natural killer cells in early human pregnancy
1 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK 2 School of Medical Education Development, Newcastle University, 3rd Floor, William Leech Building, NE2 4HH, Newcastle upon Tyne, UK
3 Correspondence address. Tel: +44-191-222-5213; Fax: +44-191-222-5066; E-mail: g.e.lash{at}ncl.ac.uk
BACKGROUND: Invasion by extravillous trophoblast into uterine decidua and myometrium with remodeling of spiral arteries is essential for normal human pregnancy and is tightly regulated. Uterine natural killer (uNK) cells appear to be a major maternal regulator of placentation through the secretion of growth factors, cytokines and proteinases.
METHOD: Matrix metalloproteinase (MMP)-2 and MMP-9 activity in placental bed biopsies was studied using in situ gelatin zymography. Expression by uNK cells of MMP-2, MMP-9 and their tissue inhibitors, TIMP-1, TIMP-2 and TIMP-3, was localized in the placental bed by immunohistochemistry. Levels of MMP-2, MMP-9, TIMP-1, TIMP-2 and TIMP-3 secreted into 24 h cell culture supernatants of isolated uNK and unseparated (total) decidual cells (8–10 and 12–14 weeks gestation, n = 10 each group) were determined by gelatin gel zymography or western blot as appropriate. RESULTS: Gelatinase activity in situ appeared greater in decidua than myometrium. uNK cells showed strong immunostaining for MMP-2 and TIMP-2. MMP-9 activity was lower in uNK cells than total decidual supernatants (8–10 weeks: P = 0.0003; 12–14 weeks: P = 0.0012). In contrast, there was no difference in MMP-2 secreted by either uNK cell or total decidual cultures.
CONCLUSIONS: uNK cells from early human pregnancy decidua possess innate protease activity, especially MMP-2, providing further evidence for a role for these cells in regulation of trophoblast invasion and spiral artery remodeling in early placentation.
Key words: uterine NK cells/early pregnancy/matrix metalloprotease/spiral artery remodeling/trophoblast invasion
Submitted on July 11, 2008; resubmitted on October 9, 2008; accepted on October 16, 2008.
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