School of Medicine, Nankai University, Tianjin 300071, China.
Biochem Biophys Res Commun. 2013 May 10;434(3):460-5. doi: 10.1016/j.bbrc.2013.04.004. Epub 2013 Apr 10.
The human leukocyte antigen G (HLA-G) is expressed on the fetal-maternal interface and plays a role in protecting fetal-derived trophoblasts from the maternal immune response, allowing trophoblasts to invade the uterus. However, HLA-G also possesses immune suppressing-independent functions. We found that HLA-G expressing BeWo choriocarcinoma cells increased cell-cell fusion compared to control BeWo cells under forskolin treatment. Regardless of forskolin treatment, the expression of fusogenic gene mRNAs, including syncytin-1, the transcription factor glial cell missing 1 (Gcm1), and beta human chorionic gonadotropin (β-hCG) were elevated. HLA-G up-regulates β-hCG production in human choriocarcinoma cells because HLA-G knockdown in JEG-3 cells induces a dramatic decrease in β-hCG compared with control cells. The defect in β-hCG production in HLA-G knocked-down cells could not be completely overcome by stimulating hCG production through increasing intracellular cAMP levels. HLA-G expressing cells have increased phosphorylation levels for extracellular signal-regulated kinase1/2 (Erk1/2) in BeWo cells. The Erk1/2 pathway is inactivated after the inhibition of HLA-G expression in JEG-3 cells. Finally, Erk1/2 inhibition was able to suppress the increased hCG production induced by HLA-G expression. Together, these data suggest novel roles for HLA-G in regulating β-hCG production via the modulation of the Erk1/2 pathway and by inducing trophoblast cell fusion.
人类白细胞抗原 G(HLA-G)在胎儿-母体界面表达,在保护胎儿来源的滋养层免受母体免疫反应方面发挥作用,使滋养层能够侵入子宫。然而,HLA-G 还具有免疫抑制作用以外的功能。我们发现,与对照 BeWo 细胞相比,在用 forskolin 处理的表达 HLA-G 的绒毛癌细胞中,细胞-细胞融合增加。无论是否用 forskolin 处理,融合基因 mRNA 的表达,包括 syncytin-1、转录因子胶质细胞缺失 1(Gcm1)和β人绒毛膜促性腺激素(β-hCG),均升高。HLA-G 上调人绒毛膜癌细胞中的β-hCG 产生,因为在 JEG-3 细胞中敲低 HLA-G 会导致与对照细胞相比,β-hCG 显著减少。通过增加细胞内 cAMP 水平刺激 hCG 产生,不能完全克服 HLA-G 敲低细胞中β-hCG 产生的缺陷。表达 HLA-G 的细胞中 BeWo 细胞的细胞外信号调节激酶 1/2(Erk1/2)磷酸化水平升高。在 JEG-3 细胞中抑制 HLA-G 表达后,Erk1/2 通路失活。最后,Erk1/2 抑制能够抑制 HLA-G 表达诱导的 hCG 产生增加。总之,这些数据表明 HLA-G 通过调节 Erk1/2 通路和诱导滋养层细胞融合,在调节β-hCG 产生方面发挥新的作用。