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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 2 812-822
Copyright © 2004 by The Endocrine Society

Tumor Necrosis Factor-{alpha} Inhibits Trophoblast Migration through Elevation of Plasminogen Activator Inhibitor-1 in First-Trimester Villous Explant Cultures

Sandra Bauer, Jürgen Pollheimer, Johannes Hartmann, Peter Husslein, John D. Aplin and Martin Knöfler

Department of Obstetrics and Gynecology (S.B., J.P., J.H., P.H., M.K.), University of Vienna, A-1090 Vienna, Austria; and School of Biological Sciences (J.D.A.), University of Manchester, M13 0JH Manchester, United Kingdom

Address all correspondence and requests for reprints to: Martin Knöfler, Department of Obstetrics and Gynecology, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna. E-mail: martin.knoefler{at}akh-wien.ac.at.

We have tested the hypothesis that elevated concentrations of TNF{alpha} could impair trophoblast invasion. Using first-trimester placental explant cultures, we have demonstrated that the cytokine inhibits in vitro migration of extravillous trophoblasts (EVT) on collagen I, and invasion through Matrigel. To elucidate the underlying mechanism, proliferation and differentiation of EVT in vitro were analyzed by immunohistochemistry of serial sections, Western blotting, zymography, ELISA, and RT-PCR from RNA pools of mechanically separated cell populations. At 24 h of cultivation in the presence or absence of TNF{alpha}, anchorage and proliferation of trophoblasts had occurred to generate cell columns containing viable, post-mitotic, differentiated EVT [positive for integrins {alpha}1 and {alpha}5, matrix metalloproteinase (MMP)-2, and human leukocyte antigen-G1; negative for proliferating cellular nuclear antigen, cytokeratin 18 neoepitope, and in 5-Bromo-2-deoxy-uridine labeling]. At 72 h, control cells had broken away from the column to migrate through the extracellular matrix; whereas, in contrast, TNF{alpha}-treated EVT remained as contiguous cell columns, despite increased MMP-9 expression. Thus, in vitro MMP9 activity appears not to be essential for trophoblast migration. Expression of plasminogen activator inhibitor (PAI)-1 was elevated in TNF{alpha}-treated EVT, and adding antibodies that inhibit PAI-1 activity restored migration, whereas tissue-inhibitor-of-metalloproteinases-1-blocking antibodies were ineffective. Induction of PAI-1 by TNF{alpha} could be related to restricted trophoblast invasion in preeclampsia.

This work was supported by Grant No. 9310 of the "Jubiläumsfond" of the Austrian National Bank.

Abbreviations: BrdU, 5-Bromo-2-deoxy-uridine; DAPI, 4'6-diamidine-2'-phenylindole dihydrochloride; ECM, extracellular matrix; ELISA, enzyme-linked immunosorbent assay; EVT, extravillous trophoblasts; HLA, human leukocyte antigen; MMP, matrix metalloproteinase; PAI, plasminogen activator inhibitor; PCNA, proliferating cellular nuclear antigen; SDS, sodium dodecyl sulfate; TBST, Tris-buffered saline with Tween 20; TIMP, tissue inhibitor of metalloproteinases; TNFR, TNF receptor; tPA, tissue-type plasminogen activator; uPA, urokinase plasminogen activator; uPAR, uPA receptor.




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