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This Article Full Text Full Text (PDF) All Versions of this Article: 73/2/237    most recent biolreprod.104.038000v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal My Folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Renaud, S. J. Articles by Graham, C. H. Search for Related Content PubMed PubMed Citation Articles by Renaud, S. J. Articles by Graham, C. H. Agricola Articles by Renaud, S. J. Articles by Graham, C. H.

Activated Macrophages Inhibit Human Cytotrophoblast Invasiveness In Vitro¹

Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada K7L 3N6

Pre-eclampsia is associated with inadequate cytotrophoblast invasion and remodeling of the uterine spiral arterioles, as well as by an aberrant maternal immune response. This study determined the effect of activated macrophages and one of its products, tumor necrosis factor (TNF)-alpha, on cytotrophoblast invasiveness. Coculture with human lipopolysaccharide-activated macrophages decreased the ability of immortalized HTR-8/ SVneo human trophoblast cells to invade through reconstituted extracellular matrix (P < 0.05). This effect of activated macrophages on trophoblast invasiveness was paralleled by abrogation of a 55-kDa caseinolytic activity corresponding to prourokinase plasminogen activator (pro-uPA) and an increased secretion of plasminogen activator inhibitor 1 (PAI1), as determined by gel zymography and ELISA, respectively. Coculture with nonactivated macrophages did not significantly affect trophoblast invasiveness or pro-uPA and PAI1 secretion. Activated macrophages secreted detectable levels of TNF, and administration of exogenous TNF significantly decreased trophoblast invasiveness (P < 0.05), increased the secretion of PAI1 (P < 0.01), and completely inhibited the pro-uPA-associated caseinolytic activity by binding to the TNF receptor 1. Moreover, addition of up to 10 ng/ml of TNF did not increase the rate of apoptosis in HTR-8/SVneo cells. Finally, the increased secretion of PAI1 by trophoblast cells cocultured with activated macrophages was significantly inhibited when a neutralizing anti-TNF antibody was added to the cocultures. These results suggest that the aberrant presence of activated macrophages around uterine vessels may contribute to inadequate trophoblast invasion and remodeling of the uterine spiral arterioles. Thus, the presence of activated macrophages may be important in the etiology of pre-eclampsia.

cytokines, immunology, placenta, pregnancy, trophoblast

² Correspondence: Charles H. Graham, Department of Anatomy and Cell Biology, Botterell Hall Room 859, Queen's University, Kingston, ON, Canada K7L 3N6. FAX: 613 533 2566; grahamc{at}post.queensu.ca

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