ASK1 promotes uterine inflammation leading to pathological preterm birth
ASK1 promotes uterine inflammation leading to pathological preterm birth
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ASK1促进子宫炎症导致病理性早产
DOI：
10.1038/s41598-020-58653-9
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发表时间：
2020
影响因子：
4.6
通讯作者：
Fujii Tomoyuki
中科院分区：
文献类型：
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作者：
Yoshikawa Midori;Iriyama Takayuki;Suzuki Kensuke;Sayama Seisuke;Tsuruga Tetsushi;Kumasawa Keiichi;Nagamatsu Takeshi;Homma Kengo;Naguro Isao;Osuga Yutaka;Ichijo Hidenori;Fujii Tomoyuki
人们普遍认为，与微生物感染相关的子宫炎症增强是早产的主要原因。然而，人们对炎症与早产相关的分子基础知之甚少。在这里，我们证明了凋亡信号调节蛋白1(ASK1)，丝裂原活化蛋白3-激酶家族的成员，促进了炎症诱导的早产，并且抑制ASK1的活性足以抑制早产。ASK1基因缺陷的妊娠小鼠的脂多糖(LPS)诱导的早产发生率较低。ASK1是诱导脂多糖诱导的与早产相关的炎症反应所必需的，包括在子宫和腹膜腔中产生促炎细胞因子。此外，通过化学遗传方法选择性抑制子宫ASK1活性，降低了脂多糖诱导的早产的发生率。此外，对人绒毛蜕膜的翻译研究表明，ASK1在内毒素诱导的JNK和p38的激活以及促炎细胞因子的产生中是必需的。我们的发现表明，ASK1的激活是导致早产的炎症诱导的原因，阻断ASK1信号可能是预防早产的一个有前途的治疗靶点。
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.