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Effect of tumour necrosis factor-alpha in combination with interferon-gamma on first trimester extravillous trophoblast invasion

Lookup NU author(s): Dr Harry Otun, Dr Gendie Lash, Barbara Innes, Dr Judith Bulmer, Dr Katsuhiko Naruse, Dr Therese Hannon, Dr Roger Searle, Professor Steve RobsonORCiD


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Successful pregnancy is dependent upon invasion of the uterine tissues by extravillous trophoblast cells (EVT). The mechanisms that control trophoblast invasion are unclear, but several cytokines and growth factors appear to be involved. We have previously demonstrated that IFN-gamma inhibits EVT invasion via a mechanism partially dependent on an increase in EVT apoptosis and decreased secretion of matrix metalloproteinase (MMP)-2. In the current study we show that TNF-alpha, both alone and in combination with IFN-gamma, inhibits EVT invasion via a mechanism associated with increased trophoblast apoptosis, decreased trophoblast proliferation and/or altered production of active proteases. TNF-alpha and its receptors, TNF-alpha RI and TNF-alpha RII, were immunolocalised in the placental bed. Uterine natural killer (uNK) cells, EVT and villous cytotrophoblast were shown to all produce TNF-alpha, and TNF-alpha receptors were primarily immunolocalised to EVT in the placental bed. TNF-alpha increased EVT apoptosis, decreased villous cytotrophoblast proliferation and increased expression of pro-MMP-9 (but not active MMP-9), urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI)-1 by EVT. The combination of TNF-alpha and IFN-gamma inhibited EVT via a mechanism associated with increased EVT apoptosis, reduced proliferation, reduced pro-MMP-2 secretion and increased secretion of uPA. TNF-alpha is one of several decidua-derived factors with the capacity to inhibit EVT invasion. The mode of activity of TNF-alpha was modified by the presence of IFN-gamma, suggesting that the local cytokine milieu may be critical in determining spatial and/or temporal changes in EVT invasion. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Publication metadata

Author(s): Otun HA, Lash GE, Innes BA, Bulmer JN, Naruse K, Hannon T, Searle RF, Robson SC

Publication type: Article

Publication status: Published

Journal: Journal of Reproductive Immunology

Year: 2011

Volume: 88

Issue: 1

Pages: 1-11

Print publication date: 26/11/2010

ISSN (print): 0165-0378

ISSN (electronic): 1872-7603

Publisher: Elsevier Ireland Ltd


DOI: 10.1016/j.jri.2010.10.003


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