Leukemia Inhibitory Factor in Human Reproduction

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Abstract
PROBLEM: Leukemia inhibitory factor (LIF) is a pleiotropic cytokine of the interleukin‐6 family and has different biological actions in various tissue systems. Although named for its ability to inhibit proliferation of a myeloid leukemic cell line by inducing differentiation, it also regulates the growth and differentiation of embryonic stem cells, primordial germ cells, peripheral neurons, osteoblasts, adipocytes, and endothelial cells. LIF is crucial for successful implantation of the embryo in mice. Currently, there is an accumulation of data about the role of LIF in human reproduction. METHOD OF STUDY: This review of the literature and of our studies focuses on the expression, regulation, and effects of LIF in the human endometrium, fallopian tube, and ovarian follicle. RESULTS: Human endometrium expresses LIF in a menstrual cycle‐dependent manner. Maximal expression is observed between days 19 and 25 of the menstrual cycle, coinciding with the time of implantation. Various cytokines and growth factors induce endometrial LIF expression in vitro. LIF receptor is expressed in endometrial tissue throughout the menstrual cycle and on human blastocysts in a stage‐dependent manner. Affecting the trophoblast differentiation pathway toward the adhesive phenotype, LIF plays a role in implantation. LIF is also expressed and secreted by the epithelial cells of the fallopian tube. Its increased expression in the tubal stromal cell cultures by the inflammatory cytokines suggests a link between salpingitis and ectopic implantation in the tube. The rising follicular fluid LIF level around the time of ovulation indicates that LIF may play a role in ovulatory events, early embryonic development, and implantation. CONCLUSIONS: There is growing evidence that LIF may be one of the entities that plays a role in human reproduction.