title: Interferon-gamma inhibits extravillous trophoblast cell invasion by a mechanism that involves both changes in apoptosis and protease levels.
abstract: BACKGROUND
  Extravillous trophoblast cell (EVT) invasion of decidua and inner third of the myometrium is critical for a successful pregnancy. Many decidual factors are likely to play a role in regulating this process, including uterine natural killer (uNK) cell-derived cytokines.
  
  
  OBJECTIVE
  1) uNK cells are a major source of IFN gamma (IFN-gamma) and 2) IFN-gamma inhibits EVT invasion via an increase in EVT apoptosis and/or a decrease in active protease levels.
  
  
  METHODS
  Total decidual and uNK cells from 8-10 wk and 12-14 wk gestational age were cultured. IFN-gamma mRNA (real-time RT-polymerase chain reaction) and protein levels (FastQuant multicytokine analysis) were determined. EVT invasion in the presence of IFN-gamma or anti-IFN-gamma-neutralizing antibodies was assessed. Trophoblast apoptosis and proliferation was assessed in explants by immunohistochemistry for M30 and Ki67. Substrate zymography was performed to determine levels of secreted MMP2, MMP9, and uPA.
  
  
  RESULTS
  mRNA and protein for IFN-gamma was detected in both total decidual and uNK cell fractions. Trophoblast invasion was inhibited by IFN-gamma. The level of M30-positive EVT was increased in the presence of IFN-gamma whereas levels of secreted MMP2 were decreased.
  
  
  CONCLUSIONS
  uNK cells are a source of IFN-gamma within early human pregnancy decidua. Mechanisms of IFN-gamma inhibition of EVT invasion include both increased EVT apoptosis and reduced levels of active proteases.
authors.affiliation: School of Surgical and Reproductive Sciences, 3rd Floor, William Leech Bldg., University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK. g.e.lash@ncl.ac.uk
authors.forename: Gendie E
authors.initials: GE
authors.lastname: Lash
authors.forename: Harry A
authors.initials: HA
authors.lastname: Otun
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Innes
authors.forename: Maureen
authors.initials: M
authors.lastname: Kirkley
authors.forename: Leandro
authors.initials: L
authors.lastname: De Oliveira
authors.forename: Roger F
authors.initials: RF
authors.lastname: Searle
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Robson
authors.forename: Judith N
authors.initials: JN
authors.lastname: Bulmer
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D049109:Cell Proliferation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D011247:Pregnancy; D014327:Trophoblasts / Q000502:physiology*; D014599:Uterus / Q000166:cytology
chemical_list: D007371:Interferon-gamma; D010447:Peptide Hydrolases