Activator protein 1 is a key terminal mediator of inflammation-induced preterm labor in mice

David A. MacIntyre*, Yun S. Lee, Roberta Migale, Bronwen R. Herbert, Simon N. Waddington, Donald Peebles, Henrik Hagberg, Mark R. Johnson, Phillip R. Bennett

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

87 Citations (Scopus)

Abstract

Activation of uterine inflammatory pathways leads to preterm labor (PTL), associated with high rates of neonatal mortality and morbidity. The transcription factors nuclear factor κB (NFκB) and activator protein 1 (AP-1) regulate key proinflammatory and procontractile genes involved in normal labor and PTL. Here we show that NFκB activation normally occurs in the mouse myometrium at gestation day E18, prior to labor, whereas AP-1 and JNK activation occurs at labor onset. Where labor was induced using the progesterone receptor antagonist RU486, NFkB and AP-1/JNK activation both occurred at the time of labor (20 h compared to 60 h in DMSO-treated controls). Using an LPS (Escherichia coli: serotype O111)-induced PTL model that selectively activates AP-1 but not NFkB, we show that myometrial AP-1 activation drives production of cytokines (Il-6, Il-8, and Il-1β), metalloproteinases (Mmp3 and Mmp10), and procontractile proteins (Cox-2 and Cx43) resulting in PTL after 7 h. Protein levels of CX43 and IL-1β, and IL-1β cleavage, were increased following LPS-induced activation of AP-1. Inhibition of JNK by SP600125 (30 mg/kg) delayed PTL by 6 h (7.5 vs. 13.5 hP<0.05). Our data reveal that NFκB activation is not a functional requirement for infection/inflammation-induced preterm labor and that AP-1 activation is sufficient to drive inflammatory pathways that cause PTL.—MacIntyre, D. A., Lee, Y. S., Migale, R., Herbert, B. R., Waddington, S. N., Peebles, D., Hagberg, H., Johnson, M. R., Bennett, P. R. Activator protein 1 is a key terminal mediator of inflammation-induced preterm labor in mice.
Original languageEnglish
Pages (from-to)2358-2368
Number of pages11
JournalFaseb Journal
Volume28
Issue number5
DOIs
Publication statusPublished - May 2014

Keywords

  • NFkB
  • infection
  • myometrium
  • progesterone
  • NF-KAPPA-B
  • HUMAN MYOMETRIAL CELLS
  • HUMAN OXYTOCIN RECEPTOR
  • HUMAN UTERINE MYOCYTES
  • PROGESTERONE-RECEPTOR
  • MECHANICAL STRETCH
  • GENE-EXPRESSION
  • TRANSCRIPTION FACTOR
  • HUMAN PARTURITION
  • AIRWAY INFLAMMATION

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