Uterine NK cells regulate endometrial bleeding in women and are suppressed by the progesterone receptor modulator asoprisnil.

Julia Wilkens, Victoria Male, Peter Ghazal, Thorsten Forster, Douglas A Gibson, Alistair Williams, S. Brito-Mutunayagam, Marie Craigon, P. Lourenco, Iain T Cameron, Kristof Chwalisz, Ashley Moffett, Hilary Critchley

Research output: Contribution to journalArticlepeer-review

Abstract

Uterine NK cells (uNK) play a role in the regulation of placentation, but their functions in nonpregnant endometrium are not understood. We have previously reported suppression of endometrial bleeding and alteration of spiral artery morphology in women exposed to asoprisnil, a progesterone receptor modulator. We now compare global endometrial gene expression in asoprisnil-treated versus control women, and we demonstrate a statistically significant reduction of genes in the IL-15 pathway, known to play a key role in uNK development and function. Suppression of IL-15 by asoprisnil was also observed at mRNA level (p < 0.05), and immunostaining for NK cell marker CD56 revealed a striking reduction of uNK in asoprisnil-treated endometrium (p < 0.001). IL-15 levels in normal endometrium are progesterone-responsive. Progesterone receptor (PR) positive stromal cells transcribe both IL-15 and IL-15RA. Thus, the response of stromal cells to progesterone will be to increase IL-15 trans-presentation to uNK, supporting their expansion and differentiation. In asoprisnil-treated endometrium, there is a marked downregulation of stromal PR expression and virtual absence of uNK. These novel findings indicate that the IL-15 pathway provides a missing link in the complex interplay among endometrial stromal cells, uNK, and spiral arteries affecting physiologic and pathologic endometrial bleeding.
Original languageEnglish
Pages (from-to)2226-2235
JournalJournal of Immunology
Volume191
Issue number5
Early online date2 Aug 2013
DOIs
Publication statusPublished - 2 Aug 2013

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