Effect of tumour necrosis factor-α in combination with interferon-γ on first trimester extravillous trophoblast invasion.
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-γ 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-α, both alone and in combination with IFN-γ, inhibits EVT invasion via a mechanism associated with increased trophoblast apoptosis, decreased trophoblast proliferation and/or altered production of active proteases. TNF-α and its receptors, TNF-αRI and TNF-αRII, were immunolocalised in the placental bed. Uterine natural killer (uNK) cells, EVT and villous cytotrophoblast were shown to all produce TNF-α, and TNF-α receptors were primarily immunolocalised to EVT in the placental bed. TNF-α 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-α and IFN-γ inhibited EVT via a mechanism associated with increased EVT apoptosis, reduced proliferation, reduced pro-MMP-2 secretion and increased secretion of uPA. TNF-α is one of several decidua-derived factors with the capacity to inhibit EVT invasion. The mode of activity of TNF-α was modified by the presence of IFN-γ, suggesting that the local cytokine milieu may be critical in determining spatial and/or temporal changes in EVT invasion.
Reproductive and Vascular Biology Group, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne NE24HH, UK.
Harry A
HA
Otun
Gendie E
GE
Lash
Barbara A
BA
Innes
Judith N
JN
Bulmer
Katsuhiko
K
Naruse
Therese
T
Hannon
Roger F
RF
Searle
Stephen C
SC
Robson
D017209:Apoptosis; D015153:Blotting, Western; D004717:Endometrium / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics; D014327:Trophoblasts / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D017395:Plasminogen Activator Inhibitor 1; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D012697:Serine Endopeptidases; C463979:pro-MMP-9 activator; D014568:Urokinase-Type Plasminogen Activator