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This version published online on June 2, 2005
Endocrinology, doi:10.1210/en.2005-0380
A more recent version of this article appeared on September 1, 2005
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Submitted on March 31, 2005
Accepted on May 24, 2005

In vivo infusion of interleukin-1{beta} and chorionic gonadotropin induces endometrial changes that mimic early pregnancy events in the baboon

Zuzana Strakova*, Patricia Mavrogianis, Xuemei Meng, Julie M. Hastings, Kevin S. Jackson, Paula Cameo, Allison Brudney, Oluwatoyin Knight, and Asgerally T. Fazleabas

Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois 60212-7313

* To whom correspondence should be addressed. E-mail: zstrakov{at}uic.edu.

Both human chorionic gonadotropin (hCG) and interleukin-1{beta} (IL-1{beta}) induce changes in the endometrium that are associated with 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/day) was infused between day 6 and 10 post ovulation (PO) to mimic blastocyst transit. On the expected day of implantation (day 10 PO) IL-1{beta} (12ng/day) or IL-1 receptor antagonist (IL-1ra, 12ng/day) was infused for an additional 5 days. Endometria were harvested on day 15 PO. Both hCG and hCG + IL-1{beta} induced marked differences in the distribution of {alpha}-smooth muscle actin, proliferation marker Ki67, decidualization marker insulin-growth factor binding protein-1 (IGFBP-1) and cyclooxygenase-1 (COX-1). The most marked effect of IL-1{beta} was the induction of IGFBP-1 protein in stromal cells close to the apical surface, while COX-1 was downregulated in the glandular epithelium. Protein arrays of uterine flushings showed significant suppression of death receptors Fas and tumor necrosis factor receptor 1 in the hCG +/- IL-1{beta} treated groups, suggesting an inhibition of apoptotis. Additionally, cytotoxic T lymphocyte antigen-4, matrix-metalloproteinase-3 and interleukin-4 were suppressed in treated animals compared with the controls. However, no differences were observed in cytokine profile between hCG and hCG+IL-1{beta} 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-1{beta}, that lead to the inhibition of apoptosis and development of an immunotolerant environment. These changes suggest that infusion of IL-1{beta} at the time of implantation into the non-pregnant baboon treated with hCG synergizes with hCG and mimics the early endometrial events associated with the presence of an embryo.
Key words: endometrium • hCG • IL-1{beta} • COX-1 • cytokine • pregnancy simulation • baboon




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