New pre-conception immune biomarkers for clinical practice: interleukin-18, interleukin-15 and TWEAK on the endometrial side, G-CSF on the follicular side

Abstract

a b s t r a c tIdentification of biomarkers of optimal uterine receptivity to the implanting embryo as well as biomarkers of oocyte competence would undoubtedly improve the efficiency of assisted reproductive technology (ART). Expression of IL-15 and IL-18 has been shown to be different in patients with failed implantation after IVF/ICSI compared with fertile controls and both correlate with local uNK (CD56+) recruitment and angiogenesis. Tumor necrosis factor weak inducer of apoptosis (TWEAK) has been described in mice as a potent early immune regulator able to protect the conceptus. The results of our studies in human suggest that TWEAK modulates the IL-18 related cytotoxicity of uNK cells. Quantification of IL-18, TWEAK and IL-15 mRNA expression by real-time PCR in endometrial tissue collected in midluteal phase of non-conception cycles allowed documentation of physiological events that occur at the time of uterine receptivity. Such information may be useful for the physician especially in patients where embryos fail to implant. Cytokine quantification may assist in understanding the mechanisms leading to repeated IVF/ICSI failure: either depletion of cytokines necessary for the apposition-adhesion, or an excess of cytokines leading to local cytotoxicity, may impair the implantation of the embryo. Other new data suggest that a pre-conception dialogue mediated by the oocyte and the follicular fluid and the oocyte may contribute to later implantation success. Follicular concentration of G-CSF appears as a useful biomarker of oocyte competence before fertilization. Moreover both in human and animal models, evidence of a role of the endometrium as a biosensor of the embryo is emerging.

Follicular Proinflammatory Cytokines and Chemokines as Markers of IVF Success

“…Our finding that levels of IL-18 were relatively low in unexplained infertility patients might then reflect an underlying perturbed immunological profile for this infertility cause. Importantly, IL-18 has been suggested to favor ovarian folliculogenesis; a positive correlation has been reported between the level of follicular IL-18 and the number of retrieved oocytes and implantation success in women with different etiologies of infertility [29, 30]. Our finding that follicular growth positively correlates with IL-18 levels indirectly supports the role of IL-18 in follicle maturation.…”

Endometrial inflammation and effect on implantation improvement and pregnancy outcome

“…Furthermore, it has been demonstrated that the endometrial levels of IL15 in IVF patients with implantation failure were lower than in the control, suggesting that this cytokine may serve as a potential preconception immune biomarkers for clinical practice (Lédée et al 2011). In agreement with these findings, another recently published study demonstrated a correlation between stromal IL15 and the number of uNK cells.…”

Effects of adipocyte-secreted factors on decidualized endometrial cells: modulation of endometrial receptivity in vitro

“…On the other hand, IL-15 has also been associated to both unexplained spontaneous abortion [6] and recurrent implantation failure [25]. We, and others, propose that during the preimplantation period, the balance of different cytokines might be more important than their absolute expression per se [23].…”