ASK1 promotes uterine inflammation leading to pathological preterm birth

Sci Rep. 2020 Feb 5;10(1):1887. doi: 10.1038/s41598-020-58653-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Lipopolysaccharides / administration & dosage
  • Lipopolysaccharides / immunology
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / immunology
  • Mice
  • Mice, Knockout
  • Peritoneal Cavity / pathology
  • Pregnancy
  • Premature Birth / immunology*
  • Premature Birth / pathology
  • Uterus / immunology*
  • Uterus / pathology

Substances

  • Cytokines
  • Lipopolysaccharides
  • MAP Kinase Kinase Kinase 5
  • Map3k5 protein, mouse