title: Uterine NK cells regulate endometrial bleeding in women and are suppressed by the progesterone receptor modulator asoprisnil.
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.
authors.affiliation: Medical Research Council Centre for Reproductive Health, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Julia
authors.initials: J
authors.lastname: Wilkens
authors.forename: Victoria
authors.initials: V
authors.lastname: Male
authors.forename: Peter
authors.initials: P
authors.lastname: Ghazal
authors.forename: Thorsten
authors.initials: T
authors.lastname: Forster
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Gibson
authors.forename: Alistair R W
authors.initials: AR
authors.lastname: Williams
authors.forename: Savita L
authors.initials: SL
authors.lastname: Brito-Mutunayagam
authors.forename: Marie
authors.initials: M
authors.lastname: Craigon
authors.forename: Paula
authors.initials: P
authors.lastname: Lourenco
authors.forename: Iain T
authors.initials: IT
authors.lastname: Cameron
authors.forename: Kristof
authors.initials: K
authors.lastname: Chwalisz
authors.forename: Ashley
authors.initials: A
authors.lastname: Moffett
authors.forename: Hilary O D
authors.initials: HO
authors.lastname: Critchley
mesh_terms: D004311:Double-Blind Method; D004717:Endometrium / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004963:Estrenes / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019409:Interleukin-15; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D007889:Leiomyoma / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D010091:Oximes / Q000627:therapeutic use*; D011980:Receptors, Progesterone / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D014594:Uterine Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D014599:Uterus
chemical_list: D004963:Estrenes; D019409:Interleukin-15; D010091:Oximes; D011980:Receptors, Progesterone; C488516:asoprisnil
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