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 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.
Highlights
It is widely accepted that enhanced uterine inflammation associated with microbial infection is a main causative factor for preterm birth
apoptosis signal-regulating kinase 1 (ASK1) activation in macrophages and other inflammatory cells is crucial for Toll-like receptor 4 (TLR4)-mediated innate immunity responses triggered by LPS, which results in the production of pro-inflammatory cytokines; ASK1-deficient mice have demonstrated resistance to LPS-induced sepsis[19]
To assess the roles of ASK1 in preterm birth, we used a preterm-birth mouse model induced by transvaginal injection of LPS into the cervix[21], which mimics the pathological condition of chorioamnionitis resulting from bacterial infection ascending from the vagina up to the uterus, in wild-type mice and ASK1−/− pregnant mice
Summary
It is widely accepted that enhanced uterine inflammation associated with microbial infection is a main causative factor for preterm birth. Excessive activation of JNK and p38 is www.nature.com/scientificreports known to trigger pathologic inflammatory responses associated with enhanced production of pro-inflammatory cytokines in the development of various diseases, including cancers, autoimmune diseases, and microbial infections[11,12,13]. Findings implicating the involvement of stress-activated signaling systems in preterm birth are limited, and a mechanism detailing how JNK and p38 receive upstream signals and induce inflammatory responses that trigger preterm birth remains unknown. We demonstrate that ASK1 is crucial for promoting infection-induced uterine inflammation leading to preterm birth by regulating the JNK and p38 pathways, based on findings from an LPS-induced preterm birth model utilizing two independent types of ASK1-genetically-engineered mice, as well as in vitro studies using human choriodecidua, implicating ASK1 as a potential therapeutic target for preterm birth
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