Librach C L, Feigenbaum S L, Bass K E, Cui T Y, Verastas N, Sadovsky Y, Quigley J P, French D L, Fisher S J
Department of Obstetrics and Gynecology, University of Toronto, Toronto General Hospital, Ontario, Canada.
J Biol Chem. 1994 Jun 24;269(25):17125-31.
During early human pregnancy, fetal cytotrophoblasts rapidly invade the uterus. This process has many similarities to tumor invasion, except that the extent and the timing of cytotrophoblast invasion are carefully regulated. Therefore, this system is particularly useful for studying mechanisms that regulate invasive processes. Previously, we showed that production and activation of the 92-kDa type IV collagenase (matrix metalloproteinase(MMP)-9) is necessary for cytotrophoblast invasion in vitro. In other systems, interleukin (IL)-1 beta is an important regulator of matrix-degrading metalloproteinases. Therefore, we investigated trophoblast production of IL-1 beta and its receptors, as well as the effects of this cytokine on cytotrophoblast metalloproteinase activity and invasion. The results showed that release of IL-1 beta parallels the invasive potential of the cytotrophoblasts; the highest levels are produced by first trimester cells and the lowest levels by term cells. Immunoprecipitation showed that cytotrophoblasts express the 80-kDa type I IL-1 receptor, suggesting that autocrine effects are possible. IL-1 beta stimulated trophoblast MMP-9 secretion (by a mechanism that required nascent mRNA and protein synthesis) as well as metalloproteinase activity and invasion of Matrigel. Increasing (by lipopolysaccharide treatment) or decreasing (by glucocorticoid treatment) IL-1 beta production had parallel effects on MMP-9 secretion, metalloproteinase activity, and invasion. Because IL-1 beta and corticosteroids are present in high concentrations at the maternal-fetal interface, normal trophoblast invasion may be regulated, in part, by their opposing actions. In contrast, stimulation of cytotrophoblast IL-1 beta secretion by lipopolysaccharide may play a role in the sequela of infected fetal membranes.
在人类妊娠早期，胎儿细胞滋养层迅速侵入子宫。这个过程与肿瘤侵袭有许多相似之处，只是细胞滋养层侵袭的程度和时间受到严格调控。因此，该系统对于研究调节侵袭过程的机制特别有用。此前，我们发现92-kDa IV型胶原酶（基质金属蛋白酶（MMP）-9）的产生和激活是细胞滋养层体外侵袭所必需的。在其他系统中，白细胞介素（IL）-1β是基质降解金属蛋白酶的重要调节因子。因此，我们研究了细胞滋养层IL-1β及其受体的产生，以及这种细胞因子对细胞滋养层金属蛋白酶活性和侵袭的影响。结果表明，IL-1β的释放与细胞滋养层的侵袭潜能平行；孕早期细胞产生的水平最高，足月细胞产生的水平最低。免疫沉淀显示细胞滋养层表达80-kDa I型IL-1受体，提示可能存在自分泌效应。IL-1β刺激细胞滋养层MMP-9分泌（通过一种需要新生mRNA和蛋白质合成的机制）以及金属蛋白酶活性和对基质胶的侵袭。增加（通过脂多糖处理）或减少（通过糖皮质激素处理）IL-1β的产生对MMP-9分泌、金属蛋白酶活性和侵袭有平行影响。由于IL-1β和皮质类固醇在母胎界面处浓度很高，正常的细胞滋养层侵袭可能部分受它们相反作用的调节。相反，脂多糖刺激细胞滋养层IL-1β分泌可能在感染胎膜的后遗症中起作用。
