Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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A more recent version of this article appeared on April 1, 2008

Published online before print January 18, 2008
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0406291

Received for publication April 25, 2006.
Revised December 20, 2007.
Accepted for publication December 21, 2007.

Article

Natural and recombinant human glycodelin activates a proapoptotic gene cascade in monocyte cells

Meng Kian Tee *{dagger}, Jean-Louis Vigne {dagger}, Jie Yu {ddagger}, and Robert N. Taylor {dagger}{ddagger}@

Departments of *Pediatrics and {dagger}Obstetrics, Gynecology and Reproductive Sciences, Center for Reproductive Sciences, University of California, San Francisco, California, USA; and {ddagger}Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia, USA

@ To whom correspondence should be addressed. E-mail: Robert.N.Taylor{at}emory.edu.


  Abstract

Glycodelin-A (GdA) is a member of the superfamily of lipocalins and the predominant glycoprotein secreted by human and primate endometrium in the secretory and early pregnancy phases. GdA can inhibit NK cell activity, T cell proliferation, and chemotaxis of monocytes. Its physiological function is thought to mediate immunotolerance at the fetomaternal interface. In the present studies, we engineered recombinant Gd (rGd) in yeast and tested its biological effects on monocyte viability. rGd, like the natural, purified endometrial GdA, is glycosylated and secreted, and they both induced apototic changes in monocytic U937 cells and primary human monocytes. Trypan blue exclusion, nucleosome release, DNA laddering, and immunocytochemistry to detect free 3`-OH DNA ends were used to characterize the effects of GdA and rGd. Using U937 cells as a model, cDNA microarray analyses revealed several pro- and antiapoptotic genes that were up- and down-regulated, respectively, in accordance with the kinetics of rGd-induced monocyte cell death. Real-time RT-PCR confirmed that Bad, Bax, and TNF-R1 gene expression were increased, whereas Bcl-2A1 and a proliferation-inducing ligand were reduced by rGd. Transfection assays in U937 cells indicated that the immunomodulatory actions of rGd were associated with NF-{kappa}B inhibition. Western blotting of U937 and primary monocyte lysates demonstrated that rGd activated caspase-8, -2, and -3 to execute programmed cell death in these cells. We postulate that infiltrating monocytes and potentially other innate immune cells of the decidua might be manipulated by this glycoprotein to enhance embryonic implantation rates or conversely, to develop novel contraceptive strategies.

Key Words: apoptosis • embryonic implantation • monocytes • pregnancy • decidua






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Copyright © 2008 by the Society for Leukocyte Biology.