MODULATION OF LEUKEMIA INHIBITORY FACTOR GENE-EXPRESSION AND PROTEIN-BIOSYNTHESIS IN HUMAN ENDOMETRIUM

Implantation is the process by which the blastocyst becomes intimately connected with the maternal endometrium/decidua. The independently de veloping preimplantation blastocyst then becomes dependent on the mate rnal environment for its continued development. Although the factors i nvolved in the regulation of blastocyst implantation are incompletely understood, recent studies strongly suggest a critical role for leukem ia inhibitory factor (LIF) in mice. We showed previously that LIF acts on human trophoblasts to shift their differentiation toward the ancho ring phenotype by increasing the synthesis of fibronectin. In the pres ent study, we first evaluated the temporal expression of LIF in the hu man endometrium in order to gain further insights into the role of LIF in human implantation. We established that LIF is expressed in the en dometrium in a menstrual cycle-dependent manner. The most abundant LIF messenger ribonucleic acid (mRNA) levels are observed in the mid- and late-luteal phase samples. LIF mRNA was also present in decidual tiss ues of first trimester of pregnancy, but levels were lower than those found in the midluteal endometrium. We then investigated the regulatio n of LIF expression in human endometrial cells in culture by cytokines , steroid hormones, and growth factors. We could not show any direct s timulatory evidence of steroid hormones (estradiol and progestins) on LIF mRNA expression or protein production by endometrial cells in cult ure. On the other hand, we showed that interleukin-1, tumor necrosis f actor-alpha, platelet-derived growth factor, epidermal growth factor, and transforming growth factor-beta are potent inducers of LIF express ion in endometrial stromal cells in culture in a concentration- and ti me-independent manner. Interferon-gamma acted to inhibit LIF expressio n induced by these cytokines. In contrast, we found high constitutive and relatively less regulated levels of LIF mRNA in the endometrial gl and cells. The timing of the expression of LIF in the endometrium sugg ests a potential role in the implantation. The regulation of the expre ssion of LIF may have an important role in the physiological and patho logical processes involving human implantation.