title: Elevated periimplantation uterine natural killer cell density in human endometrium is associated with impaired corticosteroid signaling in decidualizing stromal cells.
abstract: 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.
authors.affiliation: Department of Reproductive Health, Clinical Science Research Institute, Warwick Medical School, University Hospital, Coventry CV2 2DX, United Kingdom. s.quenby@warwick.ac.uk.
authors.forename: Keiji
authors.initials: K
authors.lastname: Kuroda
authors.forename: Radha
authors.initials: R
authors.lastname: Venkatakrishnan
authors.forename: Sean
authors.initials: S
authors.lastname: James
authors.forename: Sandra
authors.initials: S
authors.lastname: Šucurovic
authors.forename: Biserka
authors.initials: B
authors.lastname: Mulac-Jericevic
authors.forename: Emma S
authors.initials: ES
authors.lastname: Lucas
authors.forename: Satoru
authors.initials: S
authors.lastname: Takeda
authors.forename: Anatoly
authors.initials: A
authors.lastname: Shmygol
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Brosens
authors.forename: Siobhan
authors.initials: S
authors.lastname: Quenby
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism; D000305:Adrenal Cortex Hormones / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D003656:Decidua / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D004717:Endometrium / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D011247:Pregnancy; D061251:Primary Cell Culture; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
chemical_list: D000305:Adrenal Cortex Hormones; D015415:Biomarkers; D018161:Receptors, Mineralocorticoid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone
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