Intercellular adhesion molecule (ICAM)-1-mediated cell-cell adhesion is essential for various immunological functions, including natural killer (NK) cell-mediated cytotoxicity against endometrium. The present study was designed to establish whether shedding of ICAM-1 from cultured endometrial stromal cells occurred and to characterize its potential functional significance in endometrial physiology and pathology. The shed sICAM-1 molecule was detected and quantified in supernatants from endometrial stromal cultures and in peritoneal fluid by a specific enzyme-linked immunosorbent assay. The results of this study indicate that cultured endometrial stromal cells constitutively shed ICAM-1 from their surface. This ability is regulated during the menstrual cycle, as it appears to be higher in the proliferative than in the secretory phase of the cycle (16.93 +/- 2.2 and 7.7 +/- 1.76 ng/ml respectively). In order to evaluate whether the release of sICAM-1 could interfere with cell-mediated lysis of endometrium we compared the determinations of sICAM-1 in endometrial supernatants with the ability of such supernatants to suppress NK cell-mediated cytotoxicity toward endometrial targets. A significant correlation (r = 0.6, P < 0.05) was found between the sICAM-1 concentration in endometrial supernatants and the percentage of inhibition of NK cell-mediated lysis exerted by the same supernatant samples. Finally, endometrial stromal shedding of sICAM-1 appears to be related to endometriosis since endometrial stromal cultures obtained from patients with advanced stages of the disease released significantly higher amounts of the soluble protein compared to the control group (P < 0.05). sICAM-1 is a soluble molecule which can interfere with immunological functions, and its shedding may be one of the mechanisms by which refluxed endometrial cells escape immunosurveillance.

The relationship between the immune and the endometrial systems has been recently suggested to be critical to the development of endometriosis. We previously showed that one of the molecules involved in the complex events that allow this interaction is the adhesion molecule intercellular adhesion molecule (ICAM)-1. This study was designed to evaluate whether differences in ICAM-1 mRNA and protein expression might exist between eutopic endometrial cells and ectopic cells derived from endometriomas. Stromal cells were dispersed from samples of endometrium and ovarian endometriomas biopsied synchronously from 24 patients with endometriosis. We established that the relative expression of ICAM transcript was significantly higher in ectopic cells than that found in cultures derived from endometrial samples. Moreover, ectopic cells demonstrated a significant overexpression of ICAM-1 protein in both its cell-bound and soluble form (sICAM-1) (P < 0.05). Interestingly, endometrial secretion of sICAM-1 was shown to vary during the menstrual cycle as proliferative phase samples released significantly higher concentrations of the soluble protein compared to the secretory phase. In contrast, this cycle-dependent pattern was absent in stromal cells derived from endometriomas. Moreover, interleukin (IL-1beta) was able to increase sICAM-1 shedding from endometrial cells in a concentration-dependent manner and this IL-1beta-mediated induction could be slightly enhanced by oestradiol. As sICAM-1 is able to interfere with ICAM-1-mediated immune functions, the release of higher concentrations from ectopic samples may be the mechanism by which ectopic endometrial cells escape immunosurveillance.

The results of this study indicate the existence of soluble non-specific factors(s) released by human endometrial cells able to interfere with NK cell killing. These factors could participate in the local regulation of the immunological mechanisms suggested to be involved in the development of endometriosis.

A predominance of T helper (Th)2-type cytokines and a weakening of Th1 responses seem to be critical for the maintenance of a successful gestation. Among Th2-type cytokines, interleukin (IL)-10 is produced by human cytotrophoblasts and defects in this production result in specific pathological conditions of pregnancy. The current opinion is that IL-10 serves to protect the fetus from a harmful maternal immune response. However, production of the cytokine and its direct effect on uterine natural killer (uNK) cells, which represent the predominant lymphocyte population infiltrating the pregnant endometrium, are largely unknown. Thus, to shed light on the cytokine network at the maternal-fetal barrier during early pregnancy, we investigated the IL-10 system in uNK cells. We showed that uNK cells express the mRNA transcripts for IL-10 and IL-10 receptor. Production of IL-10 by the uNK cells was enhanced by both IL-2 and IL-12. Treatment with IL-10 alone enhanced uNK cell cytotoxic activity. In contrast, the cytokine did not modify the basal or stimulated production of interferon (IFN)-gamma by uNK. Thus, IL-10 does not act as a direct antagonist of uNK cell function and activation. However, IL-10 produced by uNK cells in response to IL-12 and IL-2 may still have a feedback inhibitory effect on the production of deleterious cytokines within the uterine microenvironment.

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