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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Activator protein 1 is a key terminal mediator of inflammation-induced preterm labor in mice
FASEB Journal, Volume 28, No. 5, Year 2014
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Description
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-1βl), metalloproteinases (Mmp3 and Mmp10), and procontractile proteins (Cox-2 and Cx43) resulting in PTL after 7 h. Protein levels of CX43 and IL-1βl, and IL-1βl 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 h P<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. © FASEB.
Authors & Co-Authors
MacIntyre, David A.
United Kingdom, London
Imperial College London
Lee, Yun Shien
United Kingdom, London
Imperial College London
Migale, Roberta
United Kingdom, London
Imperial College London
Herbert, Bronwen R.
United Kingdom, London
Imperial College London
Waddington, Simon N.
United Kingdom, London
University College London
South Africa, Johannesburg
School of Pathology
Peebles, Donald M.
United Kingdom, London
University College London
Hagberg, Henrik E.
Sweden, Gothenburg
Göteborgs Universitet
United Kingdom, London
King's College London
Johnson, Mark Richard
United Kingdom, London
Imperial College London
United Kingdom, London
Chelsea and Westminster Hospital
Bennett, Phillip Robert
United Kingdom, London
Imperial College London
Statistics
Citations: 92
Authors: 9
Affiliations: 6
Identifiers
Doi:
10.1096/fj.13-247783
ISSN:
08926638
Research Areas
Cancer
Maternal And Child Health