Biol Reprod Keystone Symposia Conference on Frontiers in Reproductive Biology & Regulation of Fertility.
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BOR - Papers in Press, published online ahead of print March 30, 2005.
Biol Reprod 2005, 10.1095/biolreprod.104.038000
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BIOLOGY OF REPRODUCTION 73, 237–243 (2005)
DOI: 10.1095/biolreprod.104.038000
© 2005 by the Society for the Study of Reproduction, Inc.

Activated Macrophages Inhibit Human Cytotrophoblast Invasiveness In Vitro1

Stephen J. Renaud , Lynne-Marie Postovit , Shannyn K. Macdonald-Goodfellow , Gail T. McDonald , Jason D. Caldwell , and Charles H. Graham 2 

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

1 Supported by grant T-4366 from the Heart and Stroke Foundation of Ontario awarded to C.H.G.

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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Copyright © 2005 by the Society for the Study of Reproduction.