Choi Jason C, Holtz Renae, Petroff Margaret G, Alfaidy Nadia, Murphy Shawn P
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
J Immunol. 2007 Feb 1;178(3):1598-607. doi: 10.4049/jimmunol.178.3.1598.
Trophoblast cells (TBCs) form the blastocyst-derived component of the placenta and play essential roles in fetal maintenance. The proinflammatory cytokine IFN-gamma plays a central role in activating cellular immunity, controlling cell proliferation, and inducing apoptosis. IFN-gamma is secreted by uterine NK cells in the placenta during pregnancy and in mice is required for proper formation of the decidual layer and remodeling of the uterine vasculature. Despite the presence of IFN-gamma in the placenta, TBCs do not express either MHC class Ia or class II Ags, and are resistant to IFN-gamma-mediated apoptosis. In this study, we demonstrate that IFN-gamma-induced expression of multiple genes is significantly reduced in human trophoblast-derived choriocarcinoma cells relative to HeLa epithelial or fibroblast cells. These results prompted us to investigate the integrity of the JAK/STAT-1 pathway in these cells. Choriocarcinoma cells and HeLa cells express comparable levels of the IFN-gamma receptor. However, tyrosine phosphorylation of JAK-2 is compromised in IFN-gamma-treated choriocarcinoma cells. Moreover, phosphorylation of STAT-1 at tyrosine 701 is substantially reduced in both IFN-gamma-treated human choriocarcinoma and primary TBCs compared with HeLa cells or primary foreskin fibroblasts. A corresponding reduction of both IFN regulatory factor 1 mRNA and protein expression was observed in IFN-gamma-treated TBCs. Treatment of choriocarcinoma cells with the tyrosine phosphatase inhibitor pervanadate significantly enhanced IFN-gamma-inducible JAK and STAT-1 tyrosine phosphorylation and select IFN-gamma-inducible gene expression. We propose that phosphatase-mediated suppression of IFN-gamma signaling in TBCs contributes to fetal maintenance by inhibiting expression of genes that could be detrimental to successful pregnancy.
滋养层细胞（TBCs）构成胎盘的胚泡衍生成分，并在维持胎儿发育中发挥重要作用。促炎细胞因子IFN-γ在激活细胞免疫、控制细胞增殖和诱导细胞凋亡中起核心作用。IFN-γ在孕期由胎盘的子宫自然杀伤细胞分泌，在小鼠中，它是蜕膜层正常形成和子宫血管重塑所必需的。尽管胎盘中存在IFN-γ，但TBCs既不表达MHC I类或II类抗原，并且对IFN-γ介导的细胞凋亡具有抗性。在本研究中，我们证明相对于HeLa上皮细胞或成纤维细胞，人滋养层来源的绒毛膜癌细胞中IFN-γ诱导的多个基因的表达显著降低。这些结果促使我们研究这些细胞中JAK/STAT-1信号通路的完整性。绒毛膜癌细胞和HeLa细胞表达相当水平的IFN-γ受体。然而，在IFN-γ处理的绒毛膜癌细胞中，JAK-2的酪氨酸磷酸化受损。此外，与HeLa细胞或原代包皮成纤维细胞相比，在IFN-γ处理的人绒毛膜癌细胞和原代TBCs中，STAT-1在酪氨酸701处的磷酸化均显著降低。在IFN-γ处理的TBCs中观察到IFN调节因子1 mRNA和蛋白表达相应降低。用酪氨酸磷酸酶抑制剂过氧钒酸盐处理绒毛膜癌细胞可显著增强IFN-γ诱导的JAK和STAT-1酪氨酸磷酸化以及选择的IFN-γ诱导基因的表达。我们提出，磷酸酶介导的TBCs中IFN-γ信号抑制通过抑制可能对成功妊娠有害的基因表达来促进胎儿发育。
