title: Toll-Like Receptor 4 Is an Essential Upstream Regulator of On-Time Parturition and Perinatal Viability in Mice.
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.
authors.affiliation: Robinson Research Institute and School of Medicine (H.H.W., C.D., P.Y.C., M.R.H., L.M.M., S.A.R.), University of Adelaide, Adelaide SA 5005, Australia; Chemical Biology Research Branch (K.C.R.), National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20892; and Departments of Obstetrics and Gynecology, Pediatrics and Physiology (D.M.O.), University of Alberta, Edmonton, Canada AB TG62S2.
authors.forename: Hanan H
authors.initials: HH
authors.lastname: Wahid
authors.affiliation: Robinson Research Institute and School of Medicine (H.H.W., C.D., P.Y.C., M.R.H., L.M.M., S.A.R.), University of Adelaide, Adelaide SA 5005, Australia; Chemical Biology Research Branch (K.C.R.), National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20892; and Departments of Obstetrics and Gynecology, Pediatrics and Physiology (D.M.O.), University of Alberta, Edmonton, Canada AB TG62S2.
authors.forename: Camilla L
authors.initials: CL
authors.lastname: Dorian
authors.affiliation: Robinson Research Institute and School of Medicine (H.H.W., C.D., P.Y.C., M.R.H., L.M.M., S.A.R.), University of Adelaide, Adelaide SA 5005, Australia; Chemical Biology Research Branch (K.C.R.), National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20892; and Departments of Obstetrics and Gynecology, Pediatrics and Physiology (D.M.O.), University of Alberta, Edmonton, Canada AB TG62S2.
authors.forename: Peck Yin
authors.initials: PY
authors.lastname: Chin
authors.affiliation: Robinson Research Institute and School of Medicine (H.H.W., C.D., P.Y.C., M.R.H., L.M.M., S.A.R.), University of Adelaide, Adelaide SA 5005, Australia; Chemical Biology Research Branch (K.C.R.), National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20892; and Departments of Obstetrics and Gynecology, Pediatrics and Physiology (D.M.O.), University of Alberta, Edmonton, Canada AB TG62S2.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.affiliation: Robinson Research Institute and School of Medicine (H.H.W., C.D., P.Y.C., M.R.H., L.M.M., S.A.R.), University of Adelaide, Adelaide SA 5005, Australia; Chemical Biology Research Branch (K.C.R.), National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20892; and Departments of Obstetrics and Gynecology, Pediatrics and Physiology (D.M.O.), University of Alberta, Edmonton, Canada AB TG62S2.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Robinson Research Institute and School of Medicine (H.H.W., C.D., P.Y.C., M.R.H., L.M.M., S.A.R.), University of Adelaide, Adelaide SA 5005, Australia; Chemical Biology Research Branch (K.C.R.), National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20892; and Departments of Obstetrics and Gynecology, Pediatrics and Physiology (D.M.O.), University of Alberta, Edmonton, Canada AB TG62S2.
authors.forename: David M
authors.initials: DM
authors.lastname: Olson
authors.affiliation: Robinson Research Institute and School of Medicine (H.H.W., C.D., P.Y.C., M.R.H., L.M.M., S.A.R.), University of Adelaide, Adelaide SA 5005, Australia; Chemical Biology Research Branch (K.C.R.), National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20892; and Departments of Obstetrics and Gynecology, Pediatrics and Physiology (D.M.O.), University of Alberta, Edmonton, Canada AB TG62S2.
authors.forename: Lachlan M
authors.initials: LM
authors.lastname: Moldenhauer
authors.affiliation: Robinson Research Institute and School of Medicine (H.H.W., C.D., P.Y.C., M.R.H., L.M.M., S.A.R.), University of Adelaide, Adelaide SA 5005, Australia; Chemical Biology Research Branch (K.C.R.), National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20892; and Departments of Obstetrics and Gynecology, Pediatrics and Physiology (D.M.O.), University of Alberta, Edmonton, Canada AB TG62S2.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Robertson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D005865:Gestational Age; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists; D036801:Parturition / Q000235:genetics*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D018045:Receptors, Oxytocin / Q000235:genetics; D011982:Receptors, Prostaglandin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D009292:Narcotic Antagonists; D018045:Receptors, Oxytocin; D011982:Receptors, Prostaglandin; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C034671:prostaglandin F2alpha receptor; D009270:Naloxone