Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
Department of Obstetrics, Miyagi Children's Hospital, Sendai 989-3126, Japan.
Int J Mol Sci. 2022 Feb 10;23(4):1955. doi: 10.3390/ijms23041955.
The serine protease inhibitor alpha1-antitrypsin (A1AT) may possess protective functions of impaired organs in a manner independent of its protease inhibitor activity. A1AT expression has been shown to fluctuate in patients with pregnancy-induced hypertension, which suggests that A1AT may play a role in the syncytialization of villous trophoblasts. A1AT expression was knocked down in primary trophoblasts. RNA was extracted from these cells and subjected to RNA-sequencing analysis to determine the levels of expression of markers of syncytialization and inflammation. In addition, A1AT protein was localized in trophoblastic cells in placental tissues. Knockdown of A1AT upregulated the expression of FOSL1 and markers of syncytialization, as well as cell fusion, whereas overexpression of A1AT had the opposite effects. FOSL1 overexpression stimulated syncytialization, similar to the effects of A1AT knock down. Inhibitors of p38MAPK and JNK reduce the expression of inflammatory factors, whereas a p38MAPK inhibitor suppressed FOSL1 expression. Collectively, these findings indicated A1AT may negatively regulate inflammatory responses by controlling the activation of p38MAPK and JNK, and that p38MAPK mediates trophoblast syncytialization by altering FOSL1 expression. Therefore, a dysfunction in A1AT could be responsible for abnormal placental formation and pregnancy-associated disorders.
丝氨酸蛋白酶抑制剂 α1-抗胰蛋白酶（A1AT）可能具有保护作用，能够保护受损器官，而不依赖于其蛋白酶抑制剂活性。已经表明，在妊娠高血压患者中，A1AT 的表达会波动，这表明 A1AT 可能在绒毛滋养层细胞的合胞体化中发挥作用。在原代滋养细胞中敲低 A1AT 的表达。从这些细胞中提取 RNA，并进行 RNA 测序分析，以确定合胞体化和炎症标志物的表达水平。此外，A1AT 蛋白在胎盘组织中的滋养细胞中被定位。敲低 A1AT 会上调 FOSL1 和合胞体化标志物的表达，以及细胞融合，而 A1AT 的过表达则会产生相反的效果。FOSL1 的过表达刺激合胞体化，类似于 A1AT 敲低的效果。p38MAPK 和 JNK 的抑制剂可降低炎症因子的表达，而 p38MAPK 抑制剂可抑制 FOSL1 的表达。总之，这些发现表明，A1AT 可能通过控制 p38MAPK 和 JNK 的激活来负调控炎症反应，而 p38MAPK 通过改变 FOSL1 的表达来介导滋养层细胞的合胞体化。因此，A1AT 的功能障碍可能导致胎盘形成异常和与妊娠相关的疾病。
