INTERLEUKIN-1-BETA REGULATES HUMAN CYTOTROPHOBLAST METALLOPROTEINASE ACTIVITY AND INVASION IN-VITRO

During early human pregnancy, fetal cytotrophoblasts rapidly invade th e uterus. This process has many similarities to tumor invasion, except that the extent and the timing of cytotrophoblast invasion are carefu lly regulated. Therefore, this system is particularly useful for study ing mechanisms that regulate invasive processes. Previously, we showed that production and activation of the 92-kDa type IV collagenase (mat rix metalloproteinase(MMP)-9) is necessary for cytotrophoblast invasio n in vitro. In other systems, interleukin (IL)-1 beta is an important regulator of matrix-degrading metalloproteinases. Therefore, we invest igated trophoblast production of IL-1 beta and its receptors, as well as the effects of this cytokine on cytotrophoblast metalloproteinase a ctivity and invasion. The results showed that release of IL-1 beta par allels the invasive potential of the cytotrophoblasts; the highest lev els are produced by first trimester cells and the lowest levels by ter m cells. Immunoprecipitation showed that cytotrophoblasts express the 80-kDa type I IL-1 receptor, suggesting that autocrine effects are pos sible. IL-1 beta stimulated trophoblast MMP-9 secretion (by a mechanis m that required nascent mRNA and protein synthesis) as well as metallo proteinase activity and invasion of Matrigel. Increasing (by lipopolys accharide treatment) or decreasing (by glucocorticoid treatment) IL-1 beta production had parallel effects on MMP-9 secretion, metalloprotei nase activity, and invasion. Because IL-1 beta and corticosteroids are present in high concentrations at the maternal-fetal interface, norma l trophoblast invasion may be regulated, in part, by their opposing ac tions. In contrast, stimulation of cytotrophoblast IL-1 beta secretion by lipopolysaccharide may play a role in the sequela of infected feta l membranes.