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

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 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.—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. FASEB J. 28, 2358–2368 (2014). http://www.fasebj.org

Specific Lipopolysaccharide Serotypes Induce Differential Maternal and Neonatal Inflammatory Responses in a Murine Model of Preterm Labor

“…This is consistent with our recent findings showing that murine PTL induced by intrauterine injection of LPS serotype O111:B4 is characterized by AP-1 activation and does not require NF-kB activation. 9 Our data, therefore, provide further evidence that AP-1 activation is a critical regulator of the terminal pathways or labor onset. However, inflammatory transcription factor activation varied greatly between LPS-serotype treatment, as did downstream activation of associated inflammatory and contraction genes and proteins.…”

“…Animals were anesthetized by isoflurane, and a laparotomy was performed as previously described. 9,30,31 Briefly, both uterine horns were exteriorized and the number of live fetuses per horn was recorded. An intrauterine injection of 20 mg [25 mL total volume in phosphate-buffered saline (PBS)] of either E. coli LPS serotype O111:B4, O55:B5, O127:B8, or O128:B12 (Sigma Aldrich, Gillingham, UK) or sterile PBS was injected into the upper right uterine horn between the first and second sacs.…”

“…We have recently shown that myometrial activation of AP-1 after LPS O111:B4 occurs as early as 1 hour after injection. 9 The onset of PTL 7 hours after injection of LPS O111:B4 may not be a sufficiently long enough time to permit development of a detectable inflammatory response in the fetal brain. Conversely, it is possible that pup brain inflammation may be detectable in animals treated with LPS O55:B5, O127:B8, or O128:B12 at later stages after injection.…”

N,N-Dimethylacetamide Significantly Attenuates LPS- and TNFα-Induced Proinflammatory Responses Via Inhibition of the Nuclear Factor Kappa B Pathway

“…It is not surprising then to see that SB202190 was able to suppress secretion of these inflammatory cytokines and mediators. Shoji et al previously reported involvement of the MAPK pathway in the production of proinflammatory cytokines in the choriodecidua (55)(56)(57). What was unexpected was that BAY 11-7082, an NF-κB inhibitor, did not have a significant effect on the secretion of these cytokines in results, together with our cell viability assays, served as the basis for using 10 mM as the highest concentration in the in vitro experiments here.…”

Novel Noncompetitive IL-1 Receptor–Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth

“…Moreover, a causal role of JNK/AP-1 was recently described wherein AP-1 activation alone was sufficient to induce labor and inhibition of JNK was sufficient to delay LPS-induced PTB (37). Correspondingly, SAPK and their target c-jun/c-fos (AP-1) have been shown to be activated in human uterine cervix at term and after delivery, suggesting a concomitant function for AP-1 in cervical ripening (57).…”