ASK1 promotes uterine inflammation leading to pathological preterm birth

Abstract

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 inflammationinduced 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. Preterm birth is a major health issue worldwide, occurring in 5-18% of all pregnancies, and is the leading cause of neonatal morbidity and mortality 1. Excessive inflammation induced by an exaggerated immune response is known to trigger preterm birth and various other complications in pregnancy 2. The key pathological mechanism underlying preterm birth is enhanced uterine inflammation associated with infection 3. Bacterial infection ascending from the vagina to the uterus, and the subsequent progression to intrauterine inflammation are the most substantially confirmed causative factors for preterm birth 4,5. Bacterial infection results in an increased production of pro-inflammatory cytokines, such as TNF-α, and triggers cervical ripening, uterine contraction, and fetal membrane rupture, all of which lead to preterm birth 6. The above is supported not only by a number of clinical findings, but also by multiple pathophysiological findings from animal models in which preterm birth was triggered by administration of lipopolysaccharides (LPS) and other bacteria-derived substances 7. However, despite intense research efforts to date, current strategies for treating preterm labor are limited to targeting bacterial infection and uterine contraction. These treatment options are insufficient with respect to improving perinatal outcomes, since increased myometrial contraction reflects the end stage of uterine inflammatory processes, which adversely affect the fetus 8. Therefore, regarding therapeutics targeting preterm birth, there is an emerging interest in blocking the inflammatory cascade leading to excessive uterine inflammation, as it induces not only uterine contraction and subsequent preterm bir...

miR-132-3p Modulates DUSP9-Dependent p38/JNK Signaling Pathways to Enhance Inflammation in the Amnion Leading to Labor

“…Jiang, et al [65] also demonstrated that DUSP9 acts a suppressor for the development of cardiac hypertrophy through the interaction and dephosphorylation of ASK1 to repress p38 and JNK signaling pathways. By activating the p38 and JNK pathways, ASK1 could facilitate infection-induced uterine inflammation leading to preterm birth [66]. Therefore, we speculate that DUSP9 may bind to and dephosphorylate ASK1 to participate in the inflammatory response and PGE2 production medicated by the p38 and JNK signaling pathways in the process of labor.…”

Identification and characterisation of spontaneous mutations causing deafness from a targeted knockout programme

“…4 a). Mutations in Map7 have been associated with male sterility [ 37 , 38 ], but Map3k5 homozygote mice have been reported to be fertile [ 39 ], suggesting that the loss of the first exon of Map7 is affecting MAP7 protein function, resulting in the observed infertility in rhme affected males. Male and female homozygotes for the rhme deletion had raised thresholds at high frequencies at 4 weeks old, and the hearing loss progressed with age (Fig.…”

ASKA technology-based pull-down method reveals a suppressive effect of ASK1 on the inflammatory NOD-RIPK2 pathway in brown adipocytes

“…In this study, we showed that ASK1 suppresses the inflammatory NOD-RIPK2 pathway and cytokine secretion in brown adipocytes. While ASK1 has been reported as a critical regulator of inflammation 23,34,52 , most of these reports demonstrated that ASK1 promotes the inflammatory response. Our finding is unique in that ASK1 suppresses the inflammatory response.…”