Abstract
BackgroundTWEAK (Tumor necrosis factor like WEAK inducer of apoptosis) is highly expressed by different immune cells and triggers multiple cellular responses, including control of angiogenesis. Our objective was to investigate its role in the human endometrium during the implantation window, using an ex-vivo endometrial microhistoculture model. Indeed, previous results suggested that basic TWEAK expression influences the IL-18 related uNK recruitment and local cytotoxicity.Methodology/Principal FindingsEndometrial biopsies were performed 7 to 9 days after the ovulation surge of women in monitored natural cycles. Biopsies were cut in micro-pieces and cultured on collagen sponge with appropriate medium. Morphology, functionality and cell death were analysed at different time of the culture. We used this ex vivo model to study mRNA expressions of NKp46 (a uNK cytotoxic receptor) and TGF-beta1 (protein which regulates uNK cytokine production) after adjunction of excess of recombinant IL-18 and either recombinant TWEAK or its antibody. NKp46 protein expression was also detailed by immunohistochemistry in selected patients with high basic mRNA level of IL-18 and either low or high mRNA level of TWEAK. The NKp46 immunostaining was stronger in patients with an IL-18 over-expression and a low TWEAK expression, when compared with patients with both IL-18 and TWEAK high expressions. We did not observe any difference for TWEAK expression when recombinant protein IL-18 or its antibody was added, or conversely, for IL-18 expression when TWEAK or its antibody was added in the culture medium. In a pro-inflammatory environment (obtained by an excess of IL-18), inhibition of TWEAK was able to increase significantly NKp46 and TGF-beta1 mRNA expressions.Conclusions/SignificanceTWEAK doesn't act on IL-18 expression but seems to control IL-18 related cytotoxicity on uNK cells when IL-18 is over-expressed. Thus, TWEAK appears as a crucial physiological modulator to prevent endometrial uNK cytotoxicity in human.
Highlights
The endometrium is remodelled throughout the menstrual cycle and exhibits only a short period of receptivity, known as the ‘implantation window’, which is crucial both for implantation and gestation and still remains poorly explored in routine reproductive medicine
We observed that IL-15 and IL-18 expressions were correlated with the local uterine natural killer cells (uNK) (CD56+) recruitment and subendometrial angiogenesis as reflected by the vascular flow index quantified by 3-D ultrasound with angiography [6]
We recently reported that TWEAK and IL-18 mRNA expression were correlated in patients with implantation failures [14]
Summary
The endometrium is remodelled throughout the menstrual cycle and exhibits only a short period of receptivity, known as the ‘implantation window’, which is crucial both for implantation and gestation and still remains poorly explored in routine reproductive medicine. Endometrium becomes receptive to blastocyst implantation 6 to 8 days after ovulation and remains receptive for 4 days (cycle days 20–24) [1] Such differentiation of the maternal compartment, under hormonal control, is essential to allow stromal cells to acquire the unique ability to regulate trophoblast invasion, to resist inflammatory and oxidative insults, and to dampen local maternal immune response. It has been proposed that uterine natural killer cells (uNK) could exert, directly or not, a positive or negative control of the early steps of implantation [3], [4] These cells can secrete and control an array of cytokines which are important in angiogenesis, placental development and in pregnancy establishment. Previous results suggested that basic TWEAK expression influences the IL-18 related uNK recruitment and local cytotoxicity
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