Macrophage-Derived IL-33 Is a Critical Factor for Placental Growth
Macrophage-Derived IL-33 Is a Critical Factor for Placental Growth
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DOI：
10.4049/jimmunol.1300490
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发表时间：
2013-10-01
影响因子：
4.4
通讯作者：
Pollheimer, Juergen
中科院分区：
文献类型：
--
作者：
Fock, Valerie;Mairhofer, Mario;Pollheimer, Juergen
IL-33是最近发现的IL-1超家族成员和跨膜型ST2(ST2L)的配体，与多种人类疾病有关，包括类风湿性关节炎、哮喘和心血管疾病。据报道，先兆子痫患者血清中天然的IL-33抑制物--可溶性ST2的水平降低。然而，IL-33在健康妊娠中的作用仍然难以捉摸。在目前的研究中，在人胎盘和蜕膜巨噬细胞的培养上清液中检测到IL-33，确认它们是子宫胎盘单位分泌IL-33的主要来源。由于流式细胞术和免疫荧光染色显示ST2L在特定的滋养层细胞群上表达，我们假设IL-33以旁分泌的方式刺激滋养层细胞。BrdU掺入实验显示，重组人IL-33显著促进胎盘组织培养的原代滋养层细胞、绒毛细胞滋养层细胞和细胞柱滋养层细胞的增殖。这些影响在加入可溶性ST2后被完全消除。有趣的是，Western印迹和免疫荧光分析表明，IL-33激活了原代滋养层细胞和胎盘外植体中的AKT和ERK1/2。PI3K(LY294002)和MEK1/2(UO126)的抑制剂有效地阻断了IL-33诱导的所有模型系统的增殖。综上所述，在IL-33中，我们第一次定义了，据我们所知，妊娠早期胎盘生长的巨噬细胞衍生调节因子。
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.