Secretion of embryonic interleukin 1, beta (IL1) seems to be the first response of the blastocyst to receptive endometrium, inducing molecular changes that are essential for attachment of the blastocyst. Herein we report that human chorionic gonadotropin (hCG), a glycoprotein hormone that plays a critical role in the initiation and maintenance of pregnancy, markedly down-regulates the expression of the decoy inhibitory IL1 receptor type II (IL1R2) in human endometrial epithelial cells. Treatment with hCG resulted in a dose-dependent decrease in IL1R2 soluble and membrane bound (mb) protein forms and mRNA steady-state levels, whereas no significant effect on the expression of the activating IL1 receptor type I (IL1R1) was seen. Cell infection with the wild-type human luteinizing hormone (LH)/CG receptor (hLHCGR) corroborated the above described data, whereas cell infection with the constitutively activated LHCGR led to similar effects on IL1R2 and IL1R1 expression without hCG treatment. Cloning of human IL1R2 gene promoter in the pGL3 luciferase reporter vector and transient transfection experiments further showed a significant dose-dependent diminution of IL1R2 promoter activity in response to hCG. These data suggest that hCG, by down-regulating the expression of IL1R2, a potent and specific inhibitor of IL1, without affecting the expression of the functional activating IL1R1, diminishes the ability of endometrial epithelial cells to counterbalance the local effects of IL1, making probably these cells more responsive to the cytokine. In view of IL1's role as an embryonic signal, these data reveal a new mechanism by which hCG sustains human pregnancy and promotes embryonic growth.