CYTOKINE REGULATION OF TROPHOBLAST FUNCTION

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In humans and primates, trophoblast secretion of chononic gonadotropin (CG) serves as the embryonic signal for maternal recognition of pregnancy. CG is a heterodimeric glycoprotein hormone composed of an alpha-subunit and a distinct CGbeta-subunit. Expression of CG occurs a few days subsequent to fertilization following differentiation of placental cytotrophoblasts into syncytiotrophoblasts. Absence of CG results in the initiation of a new menstrual cycle. Cytokines have been reported to play a role in regulating secretion of CG and have been postulated to modulate cytotrophoblast differentiation. Of these cytokines, interleukin- 6 (IL-6) and leukemia inhibitory factor (LIF; members of the same cytokine family) have been shown to have important roles during pregnancy. LIF is produced by the uterus at the time of blastocyst implantation and can stimulate trophectoderm proliferation in vitro. IL-6 is secreted from a number of cell types within and outside the uteroplacental unit including trophoblasts themselves and as such can act in an autocrine manner to induce secretion of CG. Trophoblast production of IL-6 is stimulated by exposure to the pro-inflammatory cytokine, IL-1. Thus, it is feasible that uterine inflammation would lead to altered secretion of CG. Furthermore, women diagnosed with the pregnancy disorder, preeclampsia, have elevated plasma levels of IL-6 and this is associated with elevated levels of CG in circulation. These and other data implicate IL-6 as being involved in trophoblast physiology as well as pathophysiology. The following specific aims are designed to begin to address the hypothesis that IL-6 regulates trophoblast differentiation and secretion of CG. Specific Aim I: Determine the role of IL-6 in regulating trophoblast proliferation and differentiation. Specific Aim II: Investigate IL-6 regulation of gene expression in trophoblasts using gene array technology. Jar choriocarcinoma cells and primary cultures of cytotrophoblasts will be used to address these aims. It is anticipated that data obtained from these experiments will establish IL-6 as being a critical regulator of trophoblast function and will begin to shed light on how IL-6 regulates trophoblast differentiation. The long term goal of these studies is to better understand maternal/fetal cytokine regulation of trophoblast function and ultimately how trophoblast secretory products modulate the maternal immune system to maintain pregnancy.