A Murine Model of Preterm Labor: Inflammatory Mediators Regulate the Production of Prostaglandin E2 and Interleukin-6 by Murine Decidua

Dudley, Donald J.; Chen, C L; Branch, D. Ware; Hammond, Elizabeth; Mitchell, Murray D.

doi:10.1095/biolreprod48.1.33

Cited by 106 publications

(37 citation statements)

References 18 publications

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“…Human IL-1␤ was a generous gift of Immunex (Seattle, WA). IL-1R antagonist (IL-1Ra) 3 was a gift from Synergen (Boulder, CO). For experimental studies, the human rTNF-␣ was provided by Dr. J. Fraser (Department of Molecular Medicine, University of Auckland, Auckland, New Zealand).…”

Section: Methodsmentioning

confidence: 99%

“…Human gestational membranes produce a number of proinflammatory cytokines (e.g., IL-1␤, TNF-␣, IL-6, and IL-8) and PGs, both constitutively and in response to inflammatory stimuli and bacterial cell wall products such as LPS (3)(4)(5)(6). At parturition, both at term as well as preterm, there is an increase in the production of these proinflammatory mediators within the uterus, but in the case of intrauterine infection, this response is significantly increased (4,7,8).…”

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confidence: 99%

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Critical Paracrine Interactions Between TNF-α and IL-10 Regulate Lipopolysaccharide-Stimulated Human Choriodecidual Cytokine and Prostaglandin E2 Production

Sato

Keelan

Mitchell

2003

The Journal of Immunology

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104

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Increased production of PGs by gestational membranes is believed to be a principal initiator of term and preterm labor. Intrauterine infection is associated with an inflammatory response in the choriodecidua characterized by elevated production of cytokines and PGs. The precise physiological significance of enhanced choriodecidual cytokine production in the mechanism of preterm labor remains uncertain. These studies were undertaken to dissect the roles and regulation of endogenous cytokines in regulating PG production by human choriodecidua. We used LPS treatment of human choriodecidual explants as our model system. In choriodecidual explant cultures, LPS (5 μg/ml) induced a rapid increase in TNF-α production, peaking at 4 h. In contrast, IL-10, IL-1β, and PGE2 production rates peaked 8, 12, and 24 h, respectively, after LPS stimulation. Immunoneutralization studies indicated that TNF-α was a primary regulator of IL-1β, IL-10, and PGE2 production, while IL-1β stimulated only PGE2 production. Neutralization of endogenous IL-10 resulted in increased TNF-α and PGE2 production. IL-10 treatment markedly decreased TNF-α and IL-1β production, but had no effect on PGE2 production. Taken together, these results demonstrate that the effects of LPS on choriodecidual cytokine and PG production are modulated by both positive and negative feedback loops. In the setting of an infection of the intrauterine, TNF-α may be a potential target for treatment intervention; IL-10 could be one such therapeutic.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Critical Paracrine Interactions Between TNF-α and IL-10 Regulate Lipopolysaccharide-Stimulated Human Choriodecidual Cytokine and Prostaglandin E2 Production

Sato

Keelan

Mitchell

2003

The Journal of Immunology

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104

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“…To test whether uterine telemetry can be used successfully to monitor labor in an induced model of preterm labor, we implanted WT mice as described above. Recordings were started on 14 dpc, and at 1:00 PM on 15 dpc the mice were injected with RU486 (100 g; Sigma, St. Louis, MO) in ethanol, as described previously (4,10). Uterine pressure was measured for 24 h.…”

Section: Animalsmentioning

confidence: 99%

In vivo measurement of intrauterine pressure by telemetry: a new approach for studying parturition in mouse models

Pierce

Kutschke²,

Cabeza

et al. 2010

Physiological Genomics

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Pierce SL, Kutschke W, Cabeza R, England SK. In vivo measurement of intrauterine pressure by telemetry: a new approach for studying parturition in mouse models. Physiol Genomics 42: 310 -316, 2010. First published May 11, 2010 doi:10.1152/physiolgenomics.00058.2010.-Transgenic and knockout mouse models have proven useful in the study of genes necessary for parturition-including genes that affect the timing and/or progression of labor contractions. However, taking full advantage of these models will require a detailed characterization of the contractile patterns in the mouse uterus. Currently the best methodology for this has been measurement of isometric tension in isolated muscle strips in vitro. However, this methodology does not provide a real-time measure of changes in uterine pressure over the course of pregnancy. Recent advances have opened the possibility of using radiotelemetric devices to more accurately and comprehensively study intrauterine pressure in vivo. We tested the effectiveness of this technology in the mouse, in both wild-type (WT) mice and a mouse model of defective parturition (SK3 channel-overexpressing mice), after surgical implant of telemetry transmitters into the uterine horn. Continuous recordings from day 18 of pregnancy through delivery revealed that WT mice typically deliver during the 12-h dark cycle after 19.5 days postcoitum. In these mice, intrauterine pressure gradually increases during this cycle, to threefold greater than that measured during the 12-h cycle before delivery. SK3-overexpressing mice, by contrast, exhibited lower intrauterine pressure over the same period. These results are consistent with the outcome of previous in vitro studies, and they indicate that telemetry is an accurate method for measuring uterine contraction, and hence parturition, in mice. The use of this technology will lead to important novel insights into changes in intrauterine pressure during the course of pregnancy. potassium channel; SK3 channel-overexpressing mice; preterm labor; uterine contraction; myometrium PRETERM DELIVERIES alone account for over 12.6% of all births in the U.S. and are associated with a high percentage (ϳ85%) of perinatal morbidity and mortality (2). Despite increased medical intervention over the past 30 years, preterm birth rates have risen by 28%-with most of these births occurring in women who do not have any of the known risk factors. Risk factors that have been identified are related to four distinct processes, each of which activates multiple signaling pathways and leads to preterm birth: precocious fetal endocrine activation, uterine overdistension, decidual bleeding, and intrauterine inflammation/infection (14).Genetically modified mouse models have served as effective systems in which to investigate the signaling pathways essential to labor-both preterm and term. Despite certain differences in parturition between human and mouse, these species are similar with respect to many of the pathways that are known to modify pregnancy outcome (8). Mouse models of alte...

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“…In the event of intrauterine infection, inflammatory cytokine expression occurs prematurely despite the antiinflammatory, progesterone-dominated environment (5,7). Similar events in rodents administered LPS in late gestation indicate the validity of mouse (m) 3 models to study the pathophysiology of preterm labor (8,9).…”

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confidence: 98%

Essential Role for IL-10 in Resistance to Lipopolysaccharide-Induced Preterm Labor in Mice

Robertson

Skinner

Care

2006

The Journal of Immunology

177

139

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IL-10 is highly expressed in the uterus and placenta and is implicated in controlling inflammation-induced pathologies of pregnancy. To investigate the role of IL-10 in regulating preterm labor, the response of IL-10 null mutant mice to low-dose LPS in late gestation was evaluated. When IL-10 null mutant C57BL/6 (IL-10−/−) and control (IL-10+/+) mice were administered LPS on day 17 of pregnancy, the dose of LPS required to elicit 50% preterm fetal loss was 10-fold lower in IL-10−/− mice than in IL-10+/+ mice. Surviving fetuses in IL-10−/− mice exhibited fetal growth restriction at lower doses of LPS than IL-10+/+ mice. Marked elevation of LPS-induced immunoactive TNF-α and IL-6 was evident in the serum, uterus, and placenta of IL-10−/− mice, and TNF-α and IL-6 mRNA expression was elevated in the uterus and placenta, but not the fetus. Serum IL-1α, IFN-γ, and IL-12p40 were increased and soluble TNFRII was diminished in the absence of IL-10, with these changes also reflected in the gestational tissues. Administration of rIL-10 to IL-10−/− mice attenuated proinflammatory cytokine synthesis and alleviated their increased susceptibility to preterm loss. Exogenous IL-10 also protected IL-10+/+ mice from fetal loss. These data show that IL-10 modulates resistance to inflammatory stimuli by down-regulating proinflammatory cytokines in the uterus and placenta. Abundance of endogenous IL-10 in gestational tissues is therefore identified as a critical determinant of resistance to preterm labor, and IL-10 may provide a useful therapeutic agent in this common condition.

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A Murine Model of Preterm Labor: Inflammatory Mediators Regulate the Production of Prostaglandin E2 and Interleukin-6 by Murine Decidua

Cited by 106 publications

References 18 publications

Critical Paracrine Interactions Between TNF-α and IL-10 Regulate Lipopolysaccharide-Stimulated Human Choriodecidual Cytokine and Prostaglandin E2 Production

Critical Paracrine Interactions Between TNF-α and IL-10 Regulate Lipopolysaccharide-Stimulated Human Choriodecidual Cytokine and Prostaglandin E2 Production

In vivo measurement of intrauterine pressure by telemetry: a new approach for studying parturition in mouse models

Essential Role for IL-10 in Resistance to Lipopolysaccharide-Induced Preterm Labor in Mice

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