CYTOKINES IN IMPLANTATION

Implantation of the blastocyst in the maternal endometrium is necessary for the initiation of mammalian pregnancy and is considered today as one of the last frontiers in reproductive endocrinology. Wilcox et al.(1) have estimated that 65% of conceptions end in unrecognized losses. These failures can be divided into failure to implant (20%), initial apposition but no adhesion or invasion (28%), and failure to develop immediately after implantation (17%). The advent of assisted reproductive techniques (ART) such as in vitro fertilization (IVF) as a treatment for infertile couples, has highlighted the importance of the implantation process, which is considered today to be the most relevant limiting factor for successful pregnancy.(2) Implantation is not a concrete event but a series of developmental phases: apposition, attachment, and invasion. Blastocyst and maternal endometrium must develop an exquisite dialogue during the so-called implantation window, which allows them to complete the implantation process. In the human, it is suggested that this period of time begins about LH day +6 and is complete by LH + 10.(3) Human blastocysts remain free in the uterine lumen until day +5,(4) and hatch by day +6.(5) Apposition, or orientation of the blastocyst within the lumen of the uterus, starts day +6 when human blastocyst is 300-400 mu m in diameter and the uterine lumen is only a potential space due to the suction of endometrial fluid by the pinopodes.(6) Adhesion of the blastocyst is a progressive phenomenon that tightens the linkages of the embryo to the lumenal epithelium and is the ''sine qua non'' for the initiation of invasion in all mammals studied.(6) In the mouse, the implantation phases are similar but the timing is different. Considering day 1 of pregnancy as the day that vaginal plug is present; apposition starts at day 41/2 of pregnancy, adhesion or attachment occurs at day 5 and invasion is completed at day 7 of pregnancy (Fig. 1). Understanding the molecular factors involved in each phase of the implantation process is critical to comprehending the mechanisms controlling reproduction. Successful implantation requires a progesterone-primed uterus and an appropriate dialog between blastocyst and endometrium. This interaction is at least in part under the control of immune mediators such as cytokines.(7,8) Cytokines are regulatory peptides or glycoproteins that can be produced by virtually every nucleated cell type in the body and they have pleiotropic regulatory effects on hematopoietic and many other cell types. Unlike hormones, cytokines usually act as intercellular (paracrine) and/or intracellular (autocrine) signals in local tissues, only occasionally spilling over into the circulation to act as endocrine mediators (for review, see reference 9). Human endometrium is an active site of cytokine production and action (for review, see reference 10), and the embryo is able to communicate with the endometrium using this same cytokine and cytokine-receptor language (for review, see reference 5). Herein we present what is known about the role of three different cytokines in the attachment or adhesion phase of the implantation process. Previously, the expression in maternal endometrium of two major cytokines appeared to be essential for implantation. Mutations in the maternal colony stimulating factor-1 (CSF-1) gene in the osteopetrotic mutant mouse compromise implantation.(11) Also, blastocyst implantation depends on the uterine expression of leukemia inhibitory factor (LIF) in mice,(12) demonstrated by the transgenic mouse model. Recently, our group reported that blockade of endometrial interleukin-1 receptor type I(IL-1R tI) by its natural antagonist interleukin-1 receptor antagonist (IL-1ra) prevents implantation in the mouse.(13)