Role of the endometrial tripod interleukin-18, -15, and -12 in inadequate uterine receptivity in patients with a history of repeated in vitro fertilization-embryo transfer failure

Fertil Steril. 2005 Mar;83(3):598-605. doi: 10.1016/j.fertnstert.2004.11.021.


Objective: To document in the endometrium the correlation among the interleukin (IL)-12, -15, and -18 mRNA and the correlation between cytokine levels, vascular status, and endometrial natural killer (NK) cell count in the context of recurrent implantation failure.

Design: A pilot study.

Setting: Department of Reproductive Immunology.

Patient(s): Women who failed to become pregnant after repeated IVF-embryo transfer and fertile control subjects.

Intervention(s): Ultrasonic evaluation and endometrial biopsy in luteal phase.

Main outcome measure(s): Uterine artery Doppler, count of uterine CD56 bright cells/field, and quantification by real-time polymerase chain reaction (PCR) to monitor IL-12 family (IL-12p40, IL-12p35, EBI3, IL-23), the IL-18 system (IL-18, IL-18R, IL18BP), and the IL-15 mRNA ratio.

Result(s): The uterine artery Doppler and the CD56 bright cell counts were significantly different in fertile and infertile patients. The mean uterine artery pulsatility index correlated significantly negatively with the IL-18/actin ratio suggesting a defect of the cytokine-dependent vascular remodeling pathway. The number of uterine CD56 bright cells was significantly correlated with the IL-15/actin and IL-18/IL-18BP ratios. Thus, IL-18 and IL-15 seems to be involved in the local recruitment and the activation of uterine natural killer (uNK) cells. IL-18 was itself correlated with IL-15 and IL-12, suggesting a local control of uNK cells activation.

Conclusion(s): The assessment of the tripod IL-12/-15/-18 shows distinct immune-related mechanisms that are involved in the broader context of inadequate uterine receptivity.

MeSH terms

  • Adult
  • Embryo Transfer*
  • Endometrium / immunology*
  • Endometrium / metabolism
  • Female
  • Fertilization in Vitro*
  • Gene Expression / immunology
  • Humans
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Interleukin-12 Subunit p35
  • Interleukin-12 Subunit p40
  • Interleukin-15 / genetics
  • Interleukin-15 / immunology
  • Interleukin-15 / metabolism
  • Interleukin-18 / genetics
  • Interleukin-18 / immunology
  • Interleukin-18 / metabolism
  • Interleukins / genetics*
  • Interleukins / immunology
  • Interleukins / metabolism
  • Killer Cells, Natural / physiology
  • Luteal Phase / immunology
  • Neovascularization, Physiologic / physiology
  • Pilot Projects
  • Pregnancy
  • Pregnancy Outcome
  • Protein Subunits / genetics
  • Protein Subunits / immunology
  • Protein Subunits / metabolism
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Treatment Failure
  • Uterus / physiology*


  • IL12A protein, human
  • Interleukin-12 Subunit p35
  • Interleukin-12 Subunit p40
  • Interleukin-15
  • Interleukin-18
  • Interleukins
  • Protein Subunits
  • RNA, Messenger
  • Interleukin-12