Reproductive Biology Unit, Department of Obstetrics and Fetal-Maternal Medicine, Medical University of Vienna, 1090 Vienna, Austria;
J Immunol. 2013 Oct 1;191(7):3734-43. doi: 10.4049/jimmunol.1300490. Epub 2013 Aug 30.
IL-33, the most recently discovered member of the IL-1 superfamily and ligand for the transmembrane form of ST2 (ST2L), has been linked to several human pathologies including rheumatoid arthritis, asthma, and cardiovascular disease. Deregulated levels of soluble ST2, the natural IL-33 inhibitor, have been reported in sera of preeclamptic patients. However, the role of IL-33 during healthy pregnancy remains elusive. In the current study, IL-33 was detected in the culture supernatants of human placental and decidual macrophages, identifying them as a major source of secreted IL-33 in the uteroplacental unit. Because flow cytometry and immunofluorescence stainings revealed membranous ST2L expression on specific trophoblast populations, we hypothesized that IL-33 stimulates trophoblasts in a paracrine manner. Indeed, BrdU incorporation assays revealed that recombinant human IL-33 significantly increased proliferation of primary trophoblasts as well as of villous cytotrophoblasts and cell column trophoblasts in placental explant cultures. These effects were fully abolished upon addition of soluble ST2. Interestingly, Western blot and immunofluorescence analyses demonstrated that IL-33 activates AKT and ERK1/2 in primary trophoblasts and placental explants. Inhibitors against PI3K (LY294002) and MEK1/2 (UO126) efficiently blocked IL-33-induced proliferation in all model systems used. In summary, with IL-33, we define for the first time, to our knowledge, a macrophage-derived regulator of placental growth during early pregnancy.
IL-33 是 IL-1 超家族中最新发现的成员，也是跨膜形式 ST2（ST2L）的配体，与包括类风湿关节炎、哮喘和心血管疾病在内的多种人类病理有关。已有研究报道，子痫前期患者血清中可溶性 ST2（IL-33 的天然抑制剂）水平失调。然而，IL-33 在健康妊娠期间的作用仍不清楚。在本研究中，我们在人胎盘和蜕膜巨噬细胞的培养上清液中检测到了 IL-33，这表明它们是子宫胎盘单位中分泌的 IL-33 的主要来源。由于流式细胞术和免疫荧光染色显示特定滋养细胞群体上存在膜 ST2L 表达，我们假设 IL-33 以旁分泌的方式刺激滋养细胞。事实上，BrdU 掺入测定表明，重组人 IL-33 显著增加了原代滋养细胞以及胎盘组织培养物中绒毛细胞滋养层和细胞柱滋养层的增殖。加入可溶性 ST2 后，这些作用完全被阻断。有趣的是，Western blot 和免疫荧光分析表明，IL-33 在原代滋养细胞和胎盘组织中激活了 AKT 和 ERK1/2。PI3K 抑制剂（LY294002）和 MEK1/2 抑制剂（UO126）有效地阻断了所有使用的模型系统中 IL-33 诱导的增殖。总之，我们首次发现，IL-33 是一种早期妊娠中胎盘生长的巨噬细胞来源调节剂。
