Objective  To analyze the expression characteristics of CD226 in placental tissues from preeclampsia (PE) patients and its biological function in trophoblast cells.

Methods CD226 mRNA transcript levels and protein expression in placental tissues from the PE patients and women with normal pregnancies were detected by qRT-PCR and immunohistochemical staining. In the trophoblast cell lines HTR8/SVneo and JAR, CD226 gene was knocked down or overexpressed, respectively, to evaluate the impact of its expression changes on cell proliferation, apoptosis, migration, and invasion. Western blot analysis was used to detect the effects of CD226 on the protein expression of TNF-α and NF-κB p65.

Results  Compared with the normal pregnancy group, the expression level of CD226 was significantly up-regulated in the placental tissues of the PE group. Knockdown of CD226 enhanced the proliferation, migration, and invasion, and suppressed apoptosis in HTR8/Svneo cells. Conversely, the overexpression of CD226 significantly inhibited the proliferation, migration, and invasion of JAR cells, while promoting apoptosis in these cells. Furthermore, Western blot analysis revealed that CD226 overexpression promoted the protein expression of TNF-α and NF-κB p65 in trophoblast cells.

Conclusion  The expression level of CD226 in placental tissues of PE is higher than that in normal pregnancy group. CD226 exerts the inhibitory effects on the proliferation, migration, and invasion, and promotes apoptosis in trophoblast cells.

1.Poon L, Shennan A, Hyett J, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: a pragmatic guide for first-trimester screening and prevention[J]. Int J Gynaecol Obstet, 2019, 146(3): 390-391. DOI: 10.1002/ijgo.12802.

2.Zhou S, Zhou N, Zhang H, et al. A prospective multicenter birth cohort in China: pregnancy health atlas[J]. Eur J Epidemiol, 2024, 39(11): 1297-1310. DOI: 10.1007/s10654-024-01157-x.

3.Hayes-ryan D, Khashan A, Hemming K, et al. Placental growth factor in assessment of women with suspected pre-eclampsia to reduce maternal morbidity: a stepped wedge cluster randomised control trial (PARROT Ireland)[J]. BMJ, 2021, 374: n1857. DOI: 10.1136/bmj.n1857.

4.Alhaddad O, Elsabaawy M, Rewisha E, et al. Survival of a case of pre-eclampsia complicated with acute fatty liver of pregnancy and acute pancreatitis[J]. Trop Doct, 2022, 52(1): 205-208. DOI: 10.1177/00494755211041870.

5.Toloza F, Derakhshan A, Männistö T, et al. Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data Meta-analysis[J]. Lancet Diabetes Endocrinol, 2022, 10(4): 243-252. DOI: 10.1016/S2213-8587(22)00007-9.

6.黄洁,韩健,郭建新,等. 子痫前期发病机制研究进展[J]. 解放军医学杂志, 2025, 50(3): 351-357. [Huang J, Han J, Guo JX, et al. Research progress in the pathogenesis of preeclampsia[J]. Medical Journal of Chinese People's Liberation Army, 2025, 50(3): 351-357.] DOI: 10.11855/j.issn.0577-7402.0891.2024.1225.

7.刘惺,王浩,丁志刚,等. ARRDC3对子痫前期中滋养层细胞侵袭的调控作用及机制分析[J]. 基因组学与应用生物学, 2020, 39(7): 3241-3248. [Liu X, Wang H, Ding ZG, et al. The regulatory effect and mechanism of ARRDC3 on trophoblast cell invasion in preeclampsia[J]. Genomics and Applied Biology, 2020, 39(7): 3241-3248.] DOI: 10.13417/j.gab.039.003241.

8.胡鑫童,凌佳怡,苏秋弟,等. CD39分子在子痫前期患者外周血CD4+ T细胞及脐静脉内皮细胞的表达及临床意义[J]. 中国免疫学杂志, 2023, 39(11): 2361-2367. [Hu XT, Ling JY, Su  QD, et al, Expressions and clinical significance of CD39 in CD4+  T cells in peripheral blood and umbilical vein endothelial cells of patients with preeclampsia[J]. Chinese Journal of Immunology, 2023, 39(11): 2361-2367.] DOI: 10.3969/j.issn.1000-484X.2023.11.020.

9.Meggyes M, Nagy DU, Feik T, et al. Examination of the TIGIT-CD226-CD112-CD155 immune checkpoint network during a healthy pregnancy[J]. Int J Mol Sci, 2022, 23(18): 10776. DOI: 10.3390/ijms231810776.

10.许瑞环,尹学念,宋世军,等. 妊娠高血压综合征患者血清对内皮细胞CD226分子表达和PDGF黏附分子的研究[J]. 中国实验诊断学, 2005, 9(3): 376-379. [Xu RH, Yin XN, Song  SJ, et al. The study of CD226 and PDGF in PIH serum treated endothelial cell[J]. Chinese Journal of Laboratory Diagnosis, 2005, 9(3): 376-379.] DOI: 10.3969/j.issn.1007-4287.2005.03.024.

11.徐丽南,王子莲,张颖,等. 子痫前期重度患者孕16~20周外周血白细胞差异基因的表达及意义[J]. 中华围产医学杂志, 2011, 14(7): 390-395. [Xu LN, Wang ZL, Zhang  Y, et al. Expression and significance of differential genes in peripheral blood leukocytes of patients with severe preeclampsia at 16-20 weeks of gestation[J]. Chinese Journal of Perinatal Medicine, 2011, 14(7): 390-395.] DOI: 10.3760/cma.j.issn.1007-9408. 2011.07.002.

12.梁结明,刘国成. 子痫前期发病机制的研究进展[J]. 国际妇产科学杂志, 2023, 50(4): 405-408, 420. [Liang JM, Liu GC. Research progress on the pathogenesis of preeclampsia[J]. J Int Obstet Gynecol, 2023, 50(4): 405-408, 420.] DOI: 10.12280/gjfckx.20230106.

13.Deer E, Herrock O, Campbell N, et al. The role of immune cells and mediators in preeclampsia[J]. Nat Rev Nephrol, 2023, 19(4): 257-270. DOI: 10.1038/s41581-022-00670-0.

14.童彤,程蔚蔚. 胎盘微环境改变与子痫前期[J]. 中国实用妇科与产科杂志, 2016, 32(4): 330-334. [Tong T, Cheng WW. Alteration of placental micro-environment and preeclampsia[J]. Chinese Journal of Practical Gynecology and Obstetrics, 2016, 32(4): 330-334.] DOI: 10.7504/fk2016030111.

15.张慧媛,刘睿言,张宇丝,等. CD226、TIGIT和CD96调节NK细胞功能参与机体抗肿瘤免疫[J]. 细胞与分子免疫学杂志, 2023, 39(9): 852-856. [Zhang HY, Liu RY, Zhang YS, et al. CD226, TIGIT and CD96 regulate NK cell function and participate in anti-tumor immunity[J]. Chinese Journal of Cellular and Molecular Immunology, 2023, 39(9): 852-856.] DOI: 10.13423/j.cnki.cjcmi.009625.

16.Ding Q, Chauvin J, Zarour H. Targeting novel inhibitory receptors in cancer immunotherapy[J]. Semin Immunol, 2020, 49: 101436. DOI: 10.1016/j.smim.2020.101436.

17.Martinet L, Smyth M. Balancing natural killer cell activation through paired receptors[J]. Nat Rev Immunol, 2015, 15(4): 243-254. DOI: 10.1038/nri3799.

18.Ma J, Hu W, Zhang D, et al. CD226 knockout alleviates high-fat diet induced obesity by suppressing proinflammatory macrophage phenotype[J]. J Transl Med, 2021, 19(1): 477. DOI: 10.1186/s12967-021-03150-4.

19.Zhou S, Xie J, Yu C, et al. CD226 deficiency promotes glutaminolysis and alleviates mitochondria damage in vascular endothelial cells under hemorrhagic shock[J]. FASEB J, 2021, 35(11): e21998. DOI: 10.1096/fj.202101134R.

20.Shapiro M, Yeh W, Longfield J, et al. CD226 deletion reduces type 1 diabetes in the NOD mouse by impairing thymocyte development and peripheral T cell activation[J]. Front Immunol, 2020, 11: 2180. DOI: 10.3389/fimmu.2020.02180.

21.Eddy A, Howell J, Chapman H, et al. Biopolymer-delivered, maternally sequestered NF-κB (nuclear factor-κB) inhibitory peptide for treatment of preeclampsia[J]. Hypertension, 2020, 75(1): 193-201. DOI: 10.1161/HYPERTENSIONAHA.119.13368.

22.周琼琼,薛秀珍. FGL2与TNF-α在子痫前期胎盘组织中的表达及临床意义[J]. 联勤军事医学, 2023, 37(10): 849-852. [Zhou QQ, Xue XZ. Expression and clinical significance of FGL2 and TNF-α in placental tissues of preeclampsia[J]. Military Medicine of Joint Logistics, 2023, 37(10): 849-852.] DOI: 10.13730/j.issn.2097-2148.2023.10.007.

23.Koper-Lenkiewicz O, Sutkowska K, Wawrusiewicz-Kurylonek N, et al. Proinflammatory cytokines (IL-1, -6, -8, -15, -17, -18, -23, TNF-α) single nucleotide polymorphisms in rheumatoid arthritis-a literature review[J]. Int J Mol Sci, 2022, 23(4): 2106. DOI: 10.3390/ijms23042106.

24.Woznicki J, Saini N, Flood P, et al. TNF-α synergises with IFN-γ to induce caspase-8-JAK1/2-STAT1-dependent death of intestinal epithelial cells[J]. Cell Death Dis, 2021, 12(10): 864. DOI: 10.1038/s41419-021-04151-3.

25.姜璐璐,朱晓琴,王慧,等. p38 MAPK在子痫前期患者外周血及胎盘组织中的表达及对TNF-α、IFN-γ的影响[J]. 中国优生与遗传杂志, 2023, 31(8): 1604-1609. [Jiang LL, Zhu XQ, Wang H, et al. Expression of p38 MAPK in peripheral blood and placenta of patients with preeclampsia and its effect on TNF-α and IFN-γ[J]. Chinese Journal of Birth Health & Heredity, 2023, 31(8): 1604-1609.] DOI: 10.13404/j.cnki.cjbhh.2023.08.029.

26.庄万祝,戚怀钻,张果,等. 早发重度子痫前期患者子宫动脉血流动态监测对胎儿生长受限的预测效能[J]. 中国妇产科临床杂志, 2023, 24(5): 526-527. [Zhuang WZ, Qi HZ, Zhang G, et  al. The predictive efficacy of dynamic monitoring of uterine artery blood flow in patients with early-onset severe preeclampsia for fetal growth restriction[J]. Chinese Journal of Clinical Obstetrics and Gynecology, 2023, 24(5): 526-527.] DOI: 10.13390/j.issn.1672-1861.2023.05.027.