{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T23:18:56Z","timestamp":1789773536353,"version":"4.0.1"},"reference-count":74,"publisher":"The Endocrine Society","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,10,1]]},"abstract":"<jats:p>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\u2212\/\u2212) 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\u2212\/\u2212 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\u2212\/\u2212 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.<\/jats:p>","DOI":"10.1210\/en.2015-1089","type":"journal-article","created":{"date-parts":[[2015,7,7]],"date-time":"2015-07-07T17:00:40Z","timestamp":1436288440000},"page":"3828-3841","source":"Crossref","is-referenced-by-count":67,"title":["Toll-Like Receptor 4 Is an Essential Upstream Regulator of On-Time Parturition and Perinatal Viability in Mice"],"prefix":"10.1210","volume":"156","author":[{"given":"Hanan H.","family":"Wahid","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla L.","family":"Dorian","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peck Yin","family":"Chin","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Hutchinson","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenner C.","family":"Rice","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Olson","sequence":"first","affiliation":[{"name":"Departments of Obstetrics and Gynecology, Pediatrics and Physiology (D.M.O.), University of Alberta, Edmonton, Canada AB TG62S2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lachlan M.","family":"Moldenhauer","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Robertson","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2015,7,7]]},"reference":[{"key":"2020071612532095700_B1","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1177\/1933719108329095","article-title":"Inflammation and pregnancy","volume":"16","author":"Challis","year":"2009","journal-title":"Reprod Sci"},{"key":"2020071612532095700_B2","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/molehr\/gag001","article-title":"Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term","volume":"9","author":"Osman","year":"2003","journal-title":"Mol Hum Reprod"},{"key":"2020071612532095700_B3","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1095\/biolreprod66.2.445","article-title":"Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term","volume":"66","author":"Young","year":"2002","journal-title":"Biol Reprod"},{"key":"2020071612532095700_B4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1046\/j.1365-3016.2001.00004.x","article-title":"Preterm delivery: a public health perspective","volume":"15","author":"Mattison","year":"2001","journal-title":"Paediatr Perinat Epidemiol"},{"key":"2020071612532095700_B5","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0140-6736(08)60074-4","article-title":"Epidemiology and causes of preterm birth","volume":"371","author":"Goldenberg","year":"2008","journal-title":"Lancet"},{"key":"2020071612532095700_B6","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/S0140-6736(05)71048-5","article-title":"4 million neonatal deaths: when? 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