Abstract
Endotoxin [lipopolysaccharide (LPS)] from Gram-negative bacteria is found in amniotic fluid in intrauterine infections that associate with the risk for spontaneous premature birth, bronchopulmonary dysplasia (BPD), and respiratory distress syndrome. Toll-like receptor 4 (TLR4) is the signaling receptor for LPS. The aim was to investigate the primary inflammatory response in mice shortly after administration of LPS to the dam (14 and 17 d of pregnancy), to the newborn, or into the amniotic fluid. The expression levels of TLR4, IL-1, tumor necrosis factor-α, IL-6, IL-10, macrophage inflammatory protein-2, and IL-1 receptor 1 were studied with ribonuclease protection assay. In addition, TLR4 protein was analyzed with Western blotting. The fetal membranes expressed TLR4 mRNA and protein and showed an acute cytokine response to LPS when LPS was administrated into the amniotic fluid. There was distinct ontogeny in the responsiveness of fetal lung to LPS: on fetal day 14 (term 20 d), both the expression of TLR4 and the acute cytokine response were undetectable 5 h after LPS; they became detectable by fetal day 17. TLR4 and the cytokine response further increased after birth. In maternal lung, the TLR4 expression was strongest and up-regulated in parallel with the induction of the cytokines. We propose that TLR4 controls the magnitude of the LPS-induced cytokine response during the perinatal period.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- BPD:
-
bronchopulmonary dysplasia
- i.a.:
-
intra-amniotic
- IL-1R1:
-
IL-1 receptor 1
- LPS:
-
lipopolysaccharide (endotoxin)
- MIP:
-
macrophage inflammatory protein
- PAMP:
-
pathogen-associated molecular pattern
- RPA:
-
ribonuclease protection assay
- TLR:
-
Toll-like receptor
- TNF:
-
tumor necrosis factor
References
Romero R, Sirtori M, Oyarzun E, Avila C, Mazor M, Callahan R, Sabo V, Athanassiadis AP, Hobbins JC 1989 Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol 161: 817–824
Romero R, Gomez R, Ghezzi F, Yoon BH, Mazor M, Edwin SS, Berry SM 1998 A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 179: 186–193
Medzhitov R, Janeway CA Jr 1997 Innate immunity: impact on the adaptive immune response. Curr Opin Immunol 9: 4–9
Anderson KV 2000 Toll signaling pathways in the innate immune response. Curr Opin Immunol 12: 13–19
Rietschel ET, Brade H 1992 Bacterial endotoxins. Sci Am 267: 54–61
Wright SD 1999 Toll, a new piece in the puzzle of innate immunity. J Exp Med 189: 605–609
Beutler B 2003 Innate immune responses to microbial poisons: discovery and function of the Toll-like receptors. Annu Rev Pharmacol Toxicol 43: 609–628
Poltorak A, He X, Smirnova I, Liu MY, Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B 1998 Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282: 2085–2088
Qureshi ST, Lariviere L, Leveque G, Clermont S, Moore KJ, Gros P, Malo D 1999 Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med 189: 615–625
Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S 1999 Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162: 3749–3752
Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K, Akira S 1999 Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11: 443–451
Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF 1998 A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 95: 588–593
Medzhitov R, Preston-Hurlburt P, Janeway CA Jr 1997 A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388: 394–397
Zhang G, Ghosh S 2001 Toll-like receptor-mediated NF-κB activation: a phylogenetically conserved paradigm in innate immunity. J Clin Invest 107: 13–19
Ghosh S, May MJ, Kopp EB 1998 NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16: 225–260
May MJ, Ghosh S 1998 Signal transduction through NF-kappa B. Immunol Today 19: 80–88
Akira S 2003 Toll-like receptor signaling. J Biol Chem 278: 38105–38108
Fukao T, Koyasu S 2003 PI3K and negative regulation of TLR signaling. Trends Immunol 24: 358–363
Nicola NA 1994 An introduction to the cytokines. In: Nicola NA (ed) Guidebook to Cytokines and Their Receptors. Oxford University Press, New York, pp 1–8
Rounioja S, Räsänen J, Glumoff V, Ojaniemi M, Mäkikallio K, Hallman M 2003 Intra-amniotic lipopolysaccharide leads to fetal cardiac dysfunction. A mouse model for fetal inflammatory response. Cardiovasc Res 60: 156–164
Sambrook T, Fritsch EF, Maniatis T 2001 Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, New York, pp 7.63–7.74
Kohmura Y, Kirikae T, Kirikae F, Nakano M, Sato I 2000 Lipopolysaccharide (LPS)-induced intra-uterine fetal death (IUFD) in mice is principally due to maternal cause but not fetal sensitivity to LPS. Microbiol Immunol 44: 897–904
Harju K, Glumoff V, Hallman M 2001 Ontogeny of Toll-like receptors Tlr2 and Tlr4 in mice. Pediatr Res 49: 81–83
Sorokin SP, McNelly NA, Hoyt RF Jr 1994 Exogenous cytokines enhance survival of macrophages from organ cultured embryonic rat tissues. Anat Rec 240: 398–406
Trapnell BC, Whitsett JA 2002 Gm-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense. Annu Rev Physiol 64: 775–802
Kramer BW, Moss TJ, Willet KE, Newnham JP, Sly PD, Kallapur SG, Ikegami M, Jobe AH 2001 Dose and time response after intraamniotic endotoxin in preterm lambs. Am J Respir Crit Care Med 164: 982–988
Newnham JP, Moss TJ, Kramer BW, Nitsos I, Ikegami M, Jobe AH 2002 The fetal maturational and inflammatory responses to different routes of endotoxin infusion in sheep. Am J Obstet Gynecol 186: 1062–1068
Hallman M, Lappalainen U, Bry K 1997 Clearance of intra-amniotic lung surfactant: uptake and utilization by the fetal rabbit lung. Am J Physiol 273: L55–L63
Bry K, Lappalainen U, Hallman M 1997 Intraamniotic interleukin-1 accelerates surfactant protein synthesis in fetal rabbits and improves lung stability after premature birth. J Clin Invest 99: 2992–2999
Watterberg KL, Demers LM, Scott SM, Murphy S 1996 Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 97: 210–215
Bry K, Hallman M, Teramo K, Waffarn F, Lappalainen U 1997 Granulocyte-macrophage colony-stimulating factor in amniotic fluid and in airway specimens of newborn. Pediatr Res 41: 105–109
Aikio O, Vuopala K, Pokela ML, Hallman M 2000 Diminished inducible nitric oxide synthase expression in fulminant early-onset neonatal pneumonia. Pediatrics 105: 1013–1019
Blahnik MJ, Ramanathan R, Riley CR, Minoo P 2001 Lipopolysaccharide-induced tumor necrosis factor-alpha and IL-10 production by lung macrophages from preterm and term neonates. Pediatr Res 50: 726–731
Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M 1999 MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 189: 1777–1782
O'Neill LA, Fitzgerald KA, Bowie AG 2003 The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol 24: 286–289
Nagai Y, Akashi S, Nagafuku M, Ogata M, Iwakura Y, Akira S, Kitamura T, Kosugi A, Kimoto M, Miyake K 2002 Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol 3: 667–672
Takeda K, Kaisho T, Akira S 2003 Toll-Like Receptors. Annu Rev Immunol 21: 335–376
Jobe AH, Bancalari E 2001 Bronchopulmonary dysplasia. Am J Respir Crit Care Med 163: 1723–1729
Jones CA, Cayabyab RG, Kwong KY, Stotts C, Wong B, Hamdan H, Minoo P, deLemos RA 1996 Undetectable interleukin (IL)-10 and persistent IL-8 expression early in hyaline membrane disease: a possible developmental basis for the predisposition to chronic lung inflammation in preterm newborns. Pediatr Res 39: 966–975
Nomura F, Akashi S, Sakao Y, Sato S, Kawai T, Matsumoto M, Nakanishi K, Kimoto M, Miyake K, Takeda K, Akira S 2000 Cutting edge: endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression. J Immunol 164: 3476–3479
Gomez R, Ghezzi F, Romero R, Munoz H, Tolosa JE, Rojas I 1995 Premature labor and intra-amniotic infection. Clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clin Perinatol 22: 281–342
Romero R, Roslansky P, Oyarzun E, Wan M, Emamian M, Novitsky TJ, Gould MJ, Hobbins JC 1988 Labor and infection. II. Bacterial endotoxin in amniotic fluid and its relationship to the onset of preterm labor. Am J Obstet Gynecol 158: 1044–1049
Lorenz E, Hallman M, Marttila R, Haataja R, Schwartz DA 2002 Association between the Asp299Gly polymorphisms in the Toll-like receptor 4 and premature births in the Finnish population. Pediatr Res 52: 373–376
Holmlund U, Cebers G, Dahlfors AR, Sandstedt B, Bremme K, Ekstrom ES, Scheynius A 2002 Expression and regulation of the pattern recognition receptors Toll-like receptor-2 and Toll-like receptor-4 in the human placenta. Immunology 107: 145–151
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by the Finnish Academy, the Biocenter Oulu, and the Foundation for Pediatric Research.
Rights and permissions
About this article
Cite this article
Harju, K., Ojaniemi, M., Rounioja, S. et al. Expression of Toll-Like Receptor 4 and Endotoxin Responsiveness in Mice during Perinatal Period. Pediatr Res 57, 644–648 (2005). https://doi.org/10.1203/01.PDR.0000156212.03459.A9
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.PDR.0000156212.03459.A9
This article is cited by
-
Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth
Scientific Reports (2016)
-
Toll-like receptor-4 in human and mouse colonic epithelium is developmentally regulated: a possible role in necrotizing enterocolitis
Pediatric Research (2015)
-
Postnatal development and LPS responsiveness of pulmonary adenosine receptor expression and of adenosine-metabolizing enzymes in mice
Pediatric Research (2014)
-
Differential effects of cytokines and corticosteroids on Toll-like receptor 2 expression and activity in human airway epithelia
Respiratory Research (2009)
