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

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

doi:10.1096/fj.13-247783

Cited by 88 publications

(85 citation statements)

References 56 publications

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“…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.…”

Section: Lps Serotypes Differentially Activate Uterine Inflammatory Psupporting

confidence: 62%

“…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.…”

Section: Murine Model Of Inflammation-induced Ptlmentioning

confidence: 99%

“…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.…”

Section: Impact Of Lps Serotypes On Pup Survival and Neonatal Brain Imentioning

confidence: 99%

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

Migale

Herbert

Lee

et al. 2015

The American Journal of Pathology

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Intrauterine inflammation is recognized as a key mediator of both normal and preterm birth but is also associated with neonatal neurological injury. Lipopolysaccharide (LPS) is often used to stimulate inflammatory pathways in animal models of infection/inflammation-induced preterm labor; however, inconsistencies in maternal and neonatal responses to LPS are frequently reported. We hypothesized that LPS serotype-specific responses may account for a portion of these inconsistencies. Four different Escherichia coli LPS serotypes (O111:B4, O55:B5, O127:B8, and O128:B12) were administered to CD1 mice via intrauterine injection at gestational day 16. Although control animals delivered at term 60 ± 15 hours postinjection (p.i.), those administered with O111:B4 delivered 7 ± 2 hours p.i., O55:B5 delivered 10 ± 3 hours p.i., O127:B8 delivered 16 ± 10 hours p.i., and O128:B12 delivered 17 ± 2 hours p.i. (means ± SD). A correlation between the onset of preterm labor and myometrial activation of the inflammatory transcription factor, activator protein 1, but not NF-κB was observed. Specific LPS serotypes induced differential activation of downstream contractile and inflammatory pathways in myometrium and neonatal pup brain. Our findings demonstrate functional disparity in inflammatory pathway activation in response to differing LPS serotypes. Selective use of LPS serotypes may represent a useful tool for targeting specific inflammatory response mechanisms in these models.

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Section: Lps Serotypes Differentially Activate Uterine Inflammatory Psupporting

confidence: 62%

Section: Murine Model Of Inflammation-induced Ptlmentioning

confidence: 99%

Section: Impact Of Lps Serotypes On Pup Survival and Neonatal Brain Imentioning

confidence: 99%

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

Migale

Herbert

Lee

et al. 2015

The American Journal of Pathology

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“…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.…”

Section: Dma Inhibits the Transcriptional Activity Of Nf-κb But Not Asupporting

confidence: 55%

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

Pekson

Poltoratsky

Gorasiya

et al. 2016

Mol Med

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Previously, we have shown that N,N-dimethylacetamide (DMA) prevents inflammation-induced preterm birth in a murine model, inhibits lipopolysaccharide (LPS)-induced increases in placental proinflammatory cytokines and upregulates the antiinflammatory cytokine interleukin-10 (IL-10). However, DMA's mechanism of action remains to be elucidated. In the current study, we investigate how DMA produces its antiinflammatory effect. Using in vitro and ex vivo models, we show that DMA suppresses secretion of proinflammatory cytokines in lipopolysaccharide (LPS)-induced RAW 264.7 cells, TNFα-challenged JEG-3 cells and LPS-stimulated human placental explants. DMA significantly attenuated secretion of TNFα, IL-6, IL-10 and granulocyte macrophage colony stimulating factor (GM-CSF) from LPS-stimulated RAW 264.7 cells; IL-6 secretion from TNFα-stimulated JEG-3 cells; and TNFα, IL-6, IL-10, GM-CSF and Interleukin-8 (IL-8) from LPS-stimulated human placental explants. We further investigated whether DMA's effect on cytokine expression involves the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. DMA (10 mM) significantly inhibited degradation of nuclear factor of kappa light polypeptide gene enhancer in B cell inhibitor α (IκBα) in LPS-stimulated RAW 264.7 cells, but there was no significant change in the expression of phosphorylated or native forms of downstream proteins in the MAPK pathway. In addition, DMA significantly attenuated luciferase activity in cells co-transfected with NF-κB-Luc reporter plasmid, but not with AP-1-Luc or CEBP-Luc reporters. Overall, our findings suggest that the antiinflammatory activity of DMA is mediated by inhibition of the NF-κB pathway via decreased IκBα degradation.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Nadeau-Vallée

Quiniou

Palacios

et al. 2015

The Journal of Immunology

101

123

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Preterm birth (PTB) is firmly linked to inflammation regardless of the presence of infection. Proinflammatory cytokines, including IL-1β, are produced in gestational tissues and can locally upregulate uterine activation proteins. Premature activation of the uterus by inflammation may lead to PTB, and IL-1 has been identified as a key inducer of this condition. However, all currently available IL-1 inhibitors are large molecules that exhibit competitive antagonism properties by inhibiting all IL-1R signaling, including transcription factor NF-κB, which conveys important physiological roles. We hereby demonstrate the efficacy of a small noncompetitive (all-d peptide) IL-1R–biased ligand, termed rytvela (labeled 101.10) in delaying IL-1β–, TLR2-, and TLR4-induced PTB in mice. The 101.10 acts without significant inhibition of NF-κB, and instead selectively inhibits IL-1R downstream stress-associated protein kinases/transcription factor c-jun and Rho GTPase/Rho-associated coiled-coil–containing protein kinase signaling pathways. The 101.10 is effective at decreasing proinflammatory and/or prolabor genes in myometrium tissue and circulating leukocytes in all PTB models independently of NF-κB, undermining NF-κB role in preterm labor. In this work, biased signaling modulation of IL-1R by 101.10 uncovers a novel strategy to prevent PTB without inhibiting NF-κB.

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

Cited by 88 publications

References 56 publications

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

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

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

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

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