Chemokine Ligand 20: A Signal for Leukocyte Recruitment During Human Ovulation?

Abstract

Ovulation is one of the cornerstones of female fertility. Disruption of the ovulatory process results in infertility, which affects approximately 10% of couples. Using a unique model in which the dominant follicle is collected across the periovulatory period in women, we have identified a leukocyte chemoattractant, chemokine ligand 20 (CCL20), in the human ovary. CCL20 mRNA is massively induced after an in vivo human chorionic gonadotropin (hCG) stimulus in granulosa (>10 000-fold) and theca (>4000-fold) cells collected during the early ovulatory (12-18 h) and late ovulatory (18-34 h) periods after hCG administration. Because the LH surge sets in motion an inflammatory reaction characterized by an influx of leukocytes and CCL20 is known to recruit leukocytes in other systems, the composition of ovarian leukocytes (CD45+) containing the CCL20 receptor CCR6 was determined immediately prior to ovulation. CD45+/CCR6+ cells were primarily natural killer cells (41%) along with B cells (12%), T cells (11%), neutrophils (10%), and monocytes (9%). Importantly, exogenous CCL20 stimulated ovarian leukocyte migration 59% within 90 minutes. Due to the difficulties in obtaining human follicles, an in vitro model was developed using granulosa-lutein cells to explore CCL20 regulation. CCL20 expression increased 40-fold within 6 hours after hCG, was regulated partially by the epithelial growth factor pathway, and was positively correlated with progesterone production. These results demonstrate that hCG dramatically increases CCL20 expression in the human ovary, that ovarian leukocytes contain the CCL20 receptor, and that CCL20 stimulates leukocyte migration. Our findings raise the prospect that CCL20 may aid in the final ovulatory events and contribute to fertility in women.

Coordinated Regulation Among Progesterone, Prostaglandins, and EGF-Like Factors in Human Ovulatory Follicles

“…The cells were acclimated in culture as described previously (23) and then treated with or without hCG (1 IU/mL). The levels of P4 in conditioned media were increased by hCG compared with controls [Fig.…”

“…Previously, we have shown that hGLC from IVF patients can respond to hCG after preincubation for 6 days (23). Indeed, these cells increased the production of P4 and PGE 2 /F 2a in response to hCG in this study.…”

“…All participants recruited had planned laparoscopic sterilization and had not taken hormonal contraceptives for at least 3 months prior to their enrollment as previously described (23). Women were also monitored by transvaginal ultrasound for two to three menstrual cycles before surgery to ascertain cycle regularity and to monitor the growth of a dominant follicle during the follicular phase.…”

Harmful and beneficial effects of inflammatory response on reproduction: sterile and pathogen-associated inflammation

“…In fact, the preovulatory follicle contains inflammatory cytokines, such as IL-1, IL-2, IL-6, TNF-a, granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage colony-stimulating factor (M-CSF) [180][181][182][183][184][185]. The LH surge produces chemokines that can attract various immune cells, such as neutrophils, monocytes, macrophages, NK cells, B cells, and T cells [186][187][188][189][190][191]. Neutrophils produce cytotoxic peptides and proteases, which can degrade the follicular wall [192,193].…”

Human Chorionic Gonadotropin-Mediated Immune Responses That Facilitate Embryo Implantation and Placentation

“…Among these leukocytes are neutrophils, monocytes, natural killer (NK) cells, dendritic cells (DCs), B cells, and T cells and for some of them, a critical role in the ovulation process has been proven (49,50). Notably, hCG also augments CCL20 expression in the ovaries and thereby stimulates a CCL20-driven leukocyte influx (51). Most likely, this function is attributed to the p-hCG isoform ( Figure 1A).…”