Interferon-γ inhibits extravillous trophoblast cell invasion by a mechanism that involves both changes in apoptosis and protease levels

• Published in: The FASEB journal 2006-12, Vol.20 (14), p.2512-2518
• Main Authors: Lash, Gendie E, Otun, Harry A, Innes, Barbara A, Kirkley, Maureen, De Oliveira, Leandro, Searle, Roger F, Robson, Stephen C, Bulmer, Judith N
• Format: Article
• Language: English
• Subjects: Apoptosis - physiology; Cell Proliferation; Female; Gene Expression Regulation; Humans; IFN‐γ; Interferon-gamma - metabolism; Killer Cells, Natural - metabolism; Peptide Hydrolases - metabolism; Pregnancy; Trophoblasts - physiology; uNK cells; Uterus - cytology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.06-6616com

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. Hypotheses: 1) uNK cells are a major source of IFN gamma (IFN-γ) and 2) IFN-γ 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-γ mRNA (real-time RT-polymerase chain reaction) and protein levels (FastQuant multicytokine analysis) were determined. EVT invasion in the presence of IFN-γ or anti-IFN-γ-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-γ was detected in both total decidual and uNK cell fractions. Trophoblast invasion was inhibited by IFN-γ. The level of M30-positive EVT was increased in the presence of IFN-γ whereas levels of secreted MMP2 were decreased. Conclusions: uNK cells are a source of IFN-γ within early human pregnancy decidua. Mechanisms of IFN-γ inhibition of EVT invasion include both increased EVT apoptosis and reduced levels of active proteases.--Lash, G. E., Otun, H. A., Innes, B. A., Kirkley, M., De Oliveira, L., Searle, R. F., Robson, S. C., Bulmer, J. N. Interferon-γ inhibits extravillous trophoblast cell invasion by a mechanism that involves both changes in apoptosis and protease levels.