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Type: Journal article
Title: Toll-like receptor 4 Is an essential upstream regulator of on-time parturition and perinatal viability in mice
Author: Wahid, H.
Dorian, C.
Chin, P.
Hutchinson, M.
Rice, K.
Olson, D.
Moldenhauer, L.
Robertson, S.
Citation: Endocrinology, 2015; 156(10):3828-3841
Publisher: Endocrine Society
Issue Date: 2015
ISSN: 0013-7227
Statement of
Hanan H. Wahid, Camilla L. Dorian, Peck Yin Chin, Mark R. Hutchinson, Kenner C. Rice, David M. Olson, Lachlan M. Moldenhauer, and Sarah A. Robertson
Abstract: An inflammatory response is instrumental in the physiological process of parturition but the upstream signals initiating inflammation are undefined. Because endogenous ligands for Toll-like receptor 4 (TLR4) are released in late gestation, we hypothesized that on-time labor requires TLR4 signaling, to trigger a cytokine and leukocyte response and accelerate the parturition cascade. In pregnant TLR4-deficient (Tlr4-/-) mice, average gestation length was extended by 13 hours and increased perinatal mortality was seen compared with wild-type controls. Quantification of cytokine and uterine activation gene expression showed that late gestation induction of Il1b, Il6, Il12b, and Tnf expression seen in control placenta and fetal membranes was disrupted in Tlr4-/- mice, and accompanied by a transient delay in expression of uterine activation genes, including prostaglandin F receptor, oxytocin receptor, and connexin-43. Leukocyte populations were altered before birth in TLR4-deficient females, with fewer neutrophils and macrophages in the placenta, and fewer dendritic cells and more regulatory T cells in the myometrium. Administration of TLR4 ligand lipopolysaccharide to pregnant wild-type mice induced cytokine expression and fetal loss, whereas Tlr4-/- pregnancies were protected. The small molecule TLR4 antagonist (+)-naloxone increased mean duration of gestation by 16 hours in wild-type mice. Collectively, these data demonstrate that TLR4 is a key upstream regulator of the inflammatory response acting to drive uterine activation and control the timing of labor. Because causal pathways for term and preterm labor converge with TLR4, interventions to manipulate TLR4 signaling may have therapeutic utility for women at risk of preterm labor, or in postterm pregnancy.
Keywords: Leukocytes
Mice, Inbred BALB C
Mice, Inbred C57BL
Animals, Newborn
Mice, Knockout
Receptors, Prostaglandin
Receptors, Oxytocin
Narcotic Antagonists
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Gene Expression
Gestational Age
Time Factors
Toll-Like Receptor 4
Rights: Copyright © 2015 by the Endocrine Society
DOI: 10.1210/en.2015-1089
Grant ID:
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