Elevated Periimplantation Uterine Natural Killer Cell Density in Human Endometrium Is Associated With Impaired Corticosteroid Signaling in Decidualizing Stromal Cells

Background: Decidualizing human endometrial stromal cells (HESCs) profoundly up-regulate 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), the enzyme that converts inert cortisone to active cortisol. We postulated that the induction of a cortisol gradient upon decidualization of the periimplantation endometrium may impact on the uterine natural killer (uNK) cell population and on local expression of corticosteroid-dependent target genes. Methods: Midluteal endometrial biopsies (n = 55) were processed for uNK cell (CD56) analysis and primary HESC cultures. The cultures remained either untreated or were decidualized for 4 or 8 days. A tissue microarray was constructed from endometria with normal (n = 18) and elevated uNK cell (n = 18) scores. An abnormal uNK cell test was defined as greater than 5% CD56+ cells in the subluminal stroma. Results: Increased uNK cell density was associated with lower endometrial expression of 11βHSD1 and mineralocorticoid receptor (MR) but not glucocorticoid receptor in vivo. Elevated uNK cell density also corresponded to impaired induction of key decidual markers (11βHSD1, prolactin, and insulin-like growth factor binding protein-1) and MR-dependent enzymes (dehydrogenase/reductase member 3 and retinol saturase) in differentiating HESC cultures. Increased uNK cell density in vivo was not associated with increased in vitro expression of either IL-15 or IL-11, two cytokines implicated in uNK cell regulation. Conclusions: Elevated levels of uNK cells in the stroma underlying the surface epithelium are associated with inadequate cortisol biosynthesis by resident decidualizing cells and suboptimal induction of key MR-dependent enzymes involved in lipid biogenesis and the retinoid transport pathway. Our observations suggest that uNK cell testing identifies those women at risk of reproductive failure due to relative uterine cortisol deficiency.

[1]  T. Li,et al.  The observer and cycle-to-cycle variability in the measurement of uterine natural killer cells by immunohistochemistry. , 2012, Journal of reproductive immunology.

[2]  Noam Stern-Ginossar,et al.  Endometrial NK Cells Are Special Immature Cells That Await Pregnancy1 , 2008, The Journal of Immunology.

[3]  J. Brosens,et al.  Decidualization of the Human Endometrium: Mechanisms, Functions, and Clinical Perspectives , 2007, Seminars in reproductive medicine.

[4]  Pengfei Li,et al.  Glucocorticoid Receptor Mediates the Effect of Progesterone on Uterine Natural Killer Cells , 2012, American journal of reproductive immunology.

[5]  Zarko Alfirevic,et al.  A feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant. , 2013, Human reproduction.

[6]  A. Kruse,et al.  DC within the pregnant mouse uterus influence growth and functional properties of uterine NK cells , 2009, European journal of immunology.

[7]  M. Molokhia,et al.  Natural Selection of Human Embryos: Impaired Decidualization of Endometrium Disables Embryo-Maternal Interactions and Causes Recurrent Pregnancy Loss , 2010, PloS one.

[8]  J. Hanna,et al.  Decidual NK cells regulate key developmental processes at the human fetal-maternal interface , 2006, Nature Medicine.

[9]  S. Kennedy,et al.  Stromal cells from endometriotic lesions and endometrium from women with endometriosis have reduced decidualization capacity. , 2006, Fertility and sterility.

[10]  D. Levy,et al.  Chemokine Gene Silencing in Decidual Stromal Cells Limits T Cell Access to the Maternal-Fetal Interface , 2012, Science.

[11]  T. Li,et al.  Expression of leukaemia inhibitory factor and interleukin 15 in endometrium of women with recurrent implantation failure after IVF; correlation with the number of endometrial natural killer cells. , 2012, Human reproduction.

[12]  S. Quenby,et al.  Prednisolone treatment reduces endometrial spiral artery development in women with recurrent miscarriage , 2011, Angiogenesis.

[13]  L. Giudice,et al.  The protein kinase A pathway-regulated transcriptome of endometrial stromal fibroblasts reveals compromised differentiation and persistent proliferative potential in endometriosis. , 2010, Endocrinology.

[14]  J. Pollard,et al.  The Uterine NK Cell Population Requires IL-15 but These Cells Are Not Required for Pregnancy nor the Resolution of a Listeria monocytogenes Infection1 , 2003, The Journal of Immunology.

[15]  J. Brosens,et al.  Disordered IL-33/ST2 Activation in Decidualizing Stromal Cells Prolongs Uterine Receptivity in Women with Recurrent Pregnancy Loss , 2012, PloS one.

[16]  S. Quenby,et al.  Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. , 2005, Fertility and sterility.

[17]  S. Robson,et al.  Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua. , 2010, Placenta.

[18]  M. Soares,et al.  Interleukin‐11 signaling is required for the differentiation of natural killer cells at the maternal–fetal interface , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[19]  O. Chazara,et al.  Maternal KIR and fetal HLA‐C: a fine balance , 2011, Journal of leukocyte biology.

[20]  Jing-Pian Peng,et al.  Retinoic acid‐metabolizing enzyme cytochrome P450 26a1 (cyp26a1) is essential for implantation: Functional study of its role in early pregnancy , 2010, Journal of cellular physiology.

[21]  S. Quenby,et al.  Localization of angiogenic growth factors and their receptors in the human endometrium throughout the menstrual cycle and in recurrent miscarriage. , 2012, Human reproduction.

[22]  A. Ashkar,et al.  Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling. , 2003, Reproduction.

[23]  Siobhan Quenby,et al.  Endometrial cell counts in recurrent miscarriage: a comparison of counting methods , 2011, Histopathology.

[24]  C. Gomez-Sanchez,et al.  11β-Hydroxysteroid dehydrogenases in human endometrium , 2006, Molecular and Cellular Endocrinology.

[25]  O. Christiansen,et al.  Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. , 2006, Human reproduction.

[26]  D. Modi,et al.  Regulation of decidualization, interleukin-11 and interleukin-15 by homeobox A 10 in endometrial stromal cells. , 2010, Journal of reproductive immunology.

[27]  Siobhan Quenby,et al.  Uterine natural killer cells and angiogenesis in recurrent reproductive failure. , 2008, Human reproduction.

[28]  J. Brosens,et al.  Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure , 2011, Nature Medicine.

[29]  Stefan Engeli,et al.  Retinol saturase promotes adipogenesis and is downregulated in obesity , 2009, Proceedings of the National Academy of Sciences.

[30]  A. Flanagan,et al.  Endometrial CD56+ natural killer cells in women with recurrent miscarriage: a histomorphometric study. , 1999, Human reproduction.

[31]  P. Saunders,et al.  Steroid receptor expression in uterine natural killer cells. , 2003, The Journal of clinical endocrinology and metabolism.

[32]  C. Kessler,et al.  Retinoic acid suppresses in-vitro decidualization of human endometrial stromal cells. , 1996, Molecular human reproduction.

[33]  Luchuan Liang,et al.  Assessment of Requirements for IL-15 and IFN Regulatory Factors in Uterine NK Cell Differentiation and Function During Pregnancy 1 , 2003, The Journal of Immunology.

[34]  D. Charnock-Jones,et al.  Progestin regulates chemokine (C-X-C motif) ligand 14 transcript level in human endometrium. , 2010, Molecular human reproduction.

[35]  J. Brosens,et al.  Induction of 11β-HSD 1 and activation of distinct mineralocorticoid receptor- and glucocorticoid receptor-dependent gene networks in decidualizing human endometrial stromal cells. , 2013, Molecular endocrinology.

[36]  J. Brosens,et al.  Transgenic overexpression of the transcription factor Nkx6.1 in β-cells of mice does not increase β-cell proliferation, β-cell mass, or improve glucose clearance , 2011 .

[37]  L. Regan,et al.  Recurrent miscarriage. , 2006, Lancet.