Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Sci Rep. 2020 Feb 5;10(1):1887. doi: 10.1038/s41598-020-58653-9.
It is widely accepted that enhanced uterine inflammation associated with microbial infection is a main causative factor for preterm birth. However, little is known about the molecular basis by which inflammation is associated with preterm birth. Here, we demonstrate that apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein 3-kinase family, facilitates inflammation-induced preterm birth and that inhibition of ASK1 activity is sufficient to suppress preterm birth. ASK1-deficient pregnant mice exhibited reduced incidence of lipopolysaccharide (LPS)-induced preterm birth. ASK1 was required for the induction of LPS-induced inflammatory responses related to preterm birth, including pro-inflammatory cytokine production in the uterus and peritoneal cavities. In addition, selective suppression of uterine ASK1 activity through a chemical genetic approach reduced the incidence of LPS-induced preterm birth. Moreover, translational studies with human choriodecidua demonstrated that ASK1 was required for LPS-induced activation of JNK and p38 and pro-inflammatory cytokine production. Our findings suggest that ASK1 activation is responsible for the induction of inflammation that leads to preterm birth and that the blockade of ASK1 signaling might be a promising therapeutic target for preventing preterm birth.
人们普遍认为，与微生物感染相关的增强的子宫炎症是导致早产的主要因素。然而，人们对炎症与早产相关的分子基础知之甚少。在这里，我们证明凋亡信号调节激酶 1（ASK1），一种丝裂原活化蛋白激酶家族的成员，促进炎症诱导的早产，并且抑制 ASK1 活性足以抑制早产。ASK1 缺陷的怀孕小鼠表现出脂多糖（LPS）诱导的早产发生率降低。ASK1 是诱导与早产相关的 LPS 诱导的炎症反应所必需的，包括子宫和腹腔中促炎细胞因子的产生。此外，通过化学遗传方法选择性抑制子宫 ASK1 活性可降低 LPS 诱导的早产发生率。此外，用人类绒毛膜蜕膜进行的转化研究表明，ASK1 是 LPS 诱导的 JNK 和 p38 的激活以及促炎细胞因子产生所必需的。我们的研究结果表明，ASK1 的激活负责诱导导致早产的炎症，并且阻断 ASK1 信号可能是预防早产的有前途的治疗靶点。
