In Vivo Infusion of Interleukin-1β and Chorionic Gonadotropin Induces Endometrial Changes that Mimic Early Pregnancy Events in the Baboon

Abstract

Both human chorionic gonadotropin (hCG) and IL-1beta induce changes in the endometrium that are associated with the establishment of pregnancy. We investigated the synergistic effect of these two embryonic signals on endometrial function using a baboon model of simulated pregnancy. Recombinant hCG (30 IU/d) was infused between d 6 and 10 post ovulation (PO) to mimic blastocyst transit. On the expected day of implantation (d 10 PO), IL-1beta (12 ng/d) or IL-1 receptor antagonist (IL-1Ra; 12 ng/d) was infused for an additional 5 d. Endometria were harvested on d 15 PO. Both hCG and hCG plus IL-1beta induced marked differences in the distribution of alpha-smooth muscle actin, proliferation marker Ki67, decidualization marker IGF-binding protein-1, and cyclooxygenase-1. The most marked effect of IL-1beta was the induction of IGF-binding protein-1 protein in stromal cells close to the apical surface, whereas cyclooxygenase-1 was down-regulated in the glandular epithelium. Protein arrays of uterine flushings showed significant suppression of death receptors, Fas and TNF receptor 1, in the hCG- with or without IL-1beta-treated groups, suggesting an inhibition of apoptosis. Additionally, cytotoxic T lymphocyte antigen-4, matrix metalloproteinase-3, and IL-4 were suppressed in treated animals compared with controls. However, no differences were observed in cytokine profile between hCG-treated and hCG- plus IL-1beta-treated baboons. This study confirms that in preparation for pregnancy, the primate endometrium undergoes both morphological and functional changes, which are modulated by hCG and IL-1beta, that lead to the inhibition of apoptosis and the development of an immunotolerant environment. These changes suggest that infusion of IL-1beta at the time of implantation into the nonpregnant baboon treated with hCG synergizes with hCG and mimics the early endometrial events associated with the presence of an embryo.

The role of chorionic gonadotropin and Notch1 in implantation

“…Studies from our laboratory indicate that the primary effect of (h)CG on stromal fibroblasts is the induction of αSMA, which is a consequence of integrins on the stromal cell membrane binding to secreted extracellular matrix proteins [16,[62][63][64]. We have demonstrated that the induction of αSMA by (h)CG may be essential in order to decrease the progesterone-regulated proliferation in these cells, and consequently initiating differentiation and a qualification to inhibit stromal cell apoptosis [65].…”

Familial molar tissues due to mutations in the inflammatory gene, NALP7, have normal postzygotic DNA methylation

“…It is, thus, possible that a defective NALP7 leads to abnormal oocyte maturation and growth and subsequently abnormal establishment of maternal methylation marks on imprinted genes. NALP7 is also known to regulate IL-1, a pleiotropic cytokine that activates a number of inflammatory pathways required for blastocyst implantation and throughout gestation (McMaster et al 1993;Rivier and Vale 1990;Strakova et al 2005). …”

L’implantation embryonnaire

“…Ainsi, dans un modèle de primate non humain, l'infusion d'hCG et d'IL1 mime les changements caractéristiques qui interviennent lors d'une grossesse et conduit à l'immunotrophisme (voir note 2) [39]. Dans un modèle murin, certaines expériences ont suggéré que l'injection du récepteur antagoniste de l'IL1, IL1Ra, réduisait considérable-ment le nombre d'embryons qui s'implantent en altérant la réceptivité de l'endomètre.…”