Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and Perinatal Research, The University of Texas Medical Branch, Galveston, Texas, USA.
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Tx, 77550.
Biol Reprod. 2018 Nov 1;99(5):1100-1112. doi: 10.1093/biolre/ioy135.
Term and preterm parturition are associated with oxidative stress (OS)-induced p38 mitogen-activated protein kinase (p38MAPK)-mediated fetal tissue (amniochorion) senescence. p38MAPK activation is a complex cell- and stimulant-dependent process. Two independent pathways of OS-induced p38MAPK activation were investigated in amnion epithelial cells (AECs) in response to cigarette smoke extract (CSE: a validated OS inducer in fetal cells): (1) the OS-mediated oxidation of apoptosis signal-regulating kinase (ASK)-1 bound Thioredoxin (Trx[SH]2) dissociates this complex, creating free and activated ASK1-signalosome and (2) transforming growth factor-mediated activation of (TGF)-beta-activated kinase (TAK)1 and TGF-beta-activated kinase 1-binding protein (TAB)1. AECs isolated from normal term, not-in-labor fetal membranes increased p38MAPK in response to CSE and downregulated it in response to antioxidant N-acetylcysteine. In AECs, both Trx and ASK1 were localized; however, they remained dissociated and not complexed, regardless of conditions. Silencing either ASK1 or its downstream effectors (MKK3/6) did not affect OS-induced p38MAPK activation. Conversely, OS increased TGF-beta's release from AECs and increased phosphorylation of both p38MAPK and TAB1. Silencing of TAB1, but not TAK1, prevented p38MAPK activation, which is indicative of TAB1-mediated autophosphorylation of p38MAPK, an activation mechanism seldom seen. OS-induced p38MAPK activation in AECs is ASK1-Trx signalosome-independent and is mediated by the TGF-beta pathway. This knowledge will help to design strategies to reduce p38MAPK activation-associated pregnancy risks.
足月产和早产与氧化应激（OS）诱导的 p38 丝裂原活化蛋白激酶（p38MAPK）介导的胎儿组织（羊膜绒毛膜）衰老有关。p38MAPK 的激活是一个复杂的细胞和刺激物依赖性过程。在对香烟烟雾提取物（CSE：胎儿细胞中有效的 OS 诱导剂）的反应中，研究了两种独立的 OS 诱导的 p38MAPK 激活途径在羊膜上皮细胞（AEC）中的作用：（1）OS 介导的凋亡信号调节激酶（ASK）-1 结合的硫氧还蛋白（Trx[SH]2）的氧化，使该复合物解离，产生游离的和激活的 ASK1-信号小体，和（2）转化生长因子介导的（TGF）-β激活激酶（TAK）1 和 TGF-β激活激酶 1 结合蛋白（TAB）1 的激活。从正常足月、未分娩的胎儿膜中分离出的 AEC 对 CSE 反应增加 p38MAPK，并对抗氧化剂 N-乙酰半胱氨酸反应降低 p38MAPK。在 AEC 中，Trx 和 ASK1 都有定位；然而，无论条件如何，它们仍然保持解离而不形成复合物。沉默 ASK1 或其下游效应物（MKK3/6）都不会影响 OS 诱导的 p38MAPK 激活。相反，OS 增加了 AEC 中 TGF-β的释放，并增加了 p38MAPK 和 TAB1 的磷酸化。沉默 TAB1，但不是 TAK1，阻止了 p38MAPK 的激活，这表明 TAB1 介导了 p38MAPK 的自磷酸化，这是一种很少见的激活机制。OS 诱导的 AEC 中的 p38MAPK 激活与 ASK1-Trx 信号小体无关，而是由 TGF-β 途径介导。这一知识将有助于设计策略来降低与 p38MAPK 激活相关的妊娠风险。
