Inflammation is associated with preterm birth. We previously described a mouse model of chronic inflammation-induced preterm birth after dental Porphyromonas gingivalis infection. The aim of this study was to employ this model system to investigate the mechanisms through which enhanced uterine contractility induces preterm birth. Messenger RNA (mRNA) encoding contraction-associated proteins, such as oxytocin receptors, was measured at various gestational time points by real-time polymerase chain reaction (PCR). Spontaneous and oxytocin-induced uterine contractile activity at gestational day 18 was assessed using a tissue organ bath. The expression levels of Toll-like receptor 2 (TLR2), TLR4, cyclooxygenase (COX)-2, nuclear factor-kappa B (NF-κB) p65, and p38 mitogen-activated protein kinase (MAPK) on gestational day 18 were also determined by real-time PCR or Western blotting. Messenger RNA encoding contraction-associated proteins was increased at gestational day 18, and the spontaneous contractile activity (1.6-fold greater area under the contraction curve) and sensitivity to oxytocin (EC50: 8.8 nM vs 2.2 nM) were enhanced in the P gingivalis group compared to those in the control group. In the P gingivalis group, COX-2 mRNA expression was not elevated in the placenta or myometrium but was upregulated 2.3-fold in the fetal membrane. The TLR2 mRNA levels in the fetal membrane were 2.7-fold higher in the P gingivalis group, whereas TLR4 levels were not elevated. Activation of the NF-κB p65 and p38 MAPK pathways was enhanced in the fetal membrane of the P gingivalis group. Thus, in mice with chronic dental P gingivalis infection, TLR2-induced inflammation in the fetal membrane leads to upregulation of uterine contractility, leading to preterm birth.
Liu L, Johnson HL, Cousens S, et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet. 2012;379(9832):2151–2161.
Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med. 2008;359(3):262–273.
Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes. In: Behrman RE, Butler AS, eds. Preterm Birth: Causes, Consequences, and Prevention. Washington, DC: National Academies Press (US); 2007.
Martin JA, Hamilton BE, Ventura SJ, Osterman MJ, Wilson EC, Mathews TJ. Births: final data for 2010. Natl Vital Stat Rep. 2012;61(1):1–72.
Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84.
Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760–765.
Romero R, Brody DT, Oyarzun E, et al. Infection and labor. III. Interleukin-1: a signal for the onset of parturition. Am J Obstet Gynecol. 1989;160(5 Pt 1):1117–1123.
Elovitz MA, Mrinalini C. Animal models of preterm birth. Trends Endocrinol Metab. 2004;15(10):479–487.
Fidel PL Jr, Romero R, Wolf N, et al. Systemic and local cytokine profiles in endotoxin-induced preterm parturition in mice. Am J Obstet Gynecol. 1994;170(5 Pt 1):1467–1475.
Nadeau-Vallee M, Quiniou C, Palacios J, et al. Novel noncompetitive IL-1 receptor-biased ligand prevents infection-and inflammation-induced preterm birth. J Immunol. 2015;195(7):3402–3415.
Wang H, Hirsch E. Bacterially-induced preterm labor and regulation of prostaglandin-metabolizing enzyme expression in mice: the role of toll-like receptor 4. Biol Reprod. 2003;69(6):1957–1963.
Sadowsky DW, Novy MJ, Witkin SS, Gravett MG. Dexamethasone or interleukin-10 blocks interleukin-1beta-induced uterine contractions in pregnant rhesus monkeys. Am J Obstet Gynecol. 2003;188(1):252–263.
Pizzo G, Guiglia R, Lo Russo L, Campisi G. Dentistry and internal medicine: from the focal infection theory to the periodontal medicine concept. Eur J Intern Med. 2010;21(6):496–502.
Seymour GJ, Ford PJ, Cullinan MP, Leishman S, Yamazaki K. Relationship between periodontal infections and systemic disease. Clin Microbiol Infect. 2007;13(suppl 4):3–10.
Davenport ES, Williams CE, Sterne JA, Murad S, Sivapathasundram V, Curtis MA. Maternal periodontal disease and preterm low birthweight: case-control study. J Dent Res. 2002;81(5):313–318.
Hasegawa-Nakamura K, Tateishi F, Nakamura T, et al. The possible mechanism of preterm birth associated with periodontopathic Porphyromonas gingivalis. J Periodontal Res. 2011;46(4):497–504.
Offenbacher S, Katz V, Fertik G, et al. Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol. 1996;67(10):1103–1113.
Ao M, Miyauchi M, Furusho H, et al. Dental infection of Porphyromonas gingivalis induces preterm birth in mice. PLoS One. 2015;10(8): e0137249.
Miyoshi H, Konishi H, Teraoka Y, et al. Enhanced expression of contractile-associated proteins and ion channels in preterm delivery model mice with chronic odontogenic Porphyromonas gingivalis infection. Reprod Sci. 2016;23(7):838–846.
Challis JRG, Gibb W, Lye SJ. Endocrine and paracrine regulation of birth at term and preterm. Endocr Rev. 2000;21(5):514–550.
Miyoshi H, Yamaoka K, Urabe S, Kudo Y. ATP-induced currents carried through P2X7 receptor in rat myometrial cells. Reprod Sci. 2012;19(12):1285–1291.
Urabe S, Miyoshi H, Fujiwara H, Yamaoka K, Kudo Y. Enhanced expression of P2X4 and P2X7 purinergic receptors in the myometrium of pregnant rats in preterm delivery models. Reprod Sci. 2009;16(12):1186–1192.
Challis JR, Sloboda DM, Alfaidy N, et al. Prostaglandins and mechanisms of preterm birth. Reproduction. 2002;124(1):1–17.
Lien E, Means TK, Heine H, et al. Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J Clin Invest. 2000;105(4):497–504.
Furusho H, Miyauchi M, Hyogo H, et al. Dental infection of Porphyromonas gingivalis exacerbates high fat diet-induced steatohepatitis in mice. J Gastroenterol. 2013;48(11):1259–1270.
Kajioka S, Takahashi-Yanaga F, Shahab N, et al. Endogenous cardiac troponin T modulates Ca(2+)-mediated smooth muscle contraction. Sci Rep. 2012;2:979.
Mesiano S. Roles of estrogen and progesterone in human parturition. Front Horm Res. 2001;27:86–104.
Young IR. The comparative physiology of parturition in mammals. Front Horm Res. 2001;27:10–30.
Chang EY, Zhang J, Sullivan S, Newman R, Singh I. N-acetylcysteine prevents preterm birth by attenuating the LPS-induced expression of contractile associated proteins in an animal model. J Matern Fetal Neonatal Med. 2012;25(11):2395–2400.
Dudley DJ. Pre-term labor: an intra-uterine inflammatory response syndrome? J Reprod Immunol. 1997;36(1-2):93–109.
Mendelson CR. Minireview: fetal-maternal hormonal signaling in pregnancy and labor. Mol Endocrinol. 2009;23(7):947–954.
Okawa T, Suzuki H, Yanagida K, et al. Effect of lipopolysaccharide on uterine contractions and prostaglandin production in pregnant rats. Am J Obstet Gynecol. 2001;184(2):84–89.
Ross RG, Sathishkumar K, Naik AK, et al. Mechanisms of lipopolysaccharide-induced changes in effects of contractile agonists on pregnant rat myometrium. Am J Obstet Gynecol. 2004;190(2):532–540.
Hajishengallis G, Tapping RI, Harokopakis E, et al. Differential interactions of fimbriae and lipopolysaccharide from Porphyromonas gingivalis with the Toll-like receptor 2-centred pattern recognition apparatus. Cell Microbiol. 2006;8(10):1557–70.
Lindstrom TM, Bennett PR. The role of nuclear factor kappa B in human labour. Reproduction. 2005;130(5):569–581.
Shoji T, Yoshida S, Mitsunari M, et al. Involvement of p38 MAP kinase in lipopolysaccharide-induced production of pro-and anti-inflammatory cytokines and prostaglandin E2 in human choriodecidua. J Reprod Immunol. 2007;75(2):82–90.
Kim YM, Romero R, Chaiworapongsa T, et al. Toll-like receptor-2 and −4 in the chorioamniotic membranes in spontaneous labor at term and in preterm parturition that are associated with chorioamnionitis. Am J Obstet Gynecol. 2004;191(4):1346–1355.
Michalowicz BS, Hodges JS, DiAngelis AJ, et al. Treatment of periodontal disease and the risk of preterm birth. N Engl J Med. 2006;355(18):1885–1894.
Polyzos NP, Polyzos IP, Zavos A, et al. Obstetric outcomes after treatment of periodontal disease during pregnancy: systematic review and meta-analysis. BMJ. 2010;341:c7017.
Xiong X, Buekens P, Goldenberg RL, Offenbacher S, Qian X. Optimal timing of periodontal disease treatment for prevention of adverse pregnancy outcomes: before or during pregnancy? Am J Obstet Gynecol. 2011;205:111–e1–6. doi:https://doi.org/10.1016/j.ajog.2011.03.017
Michalowicz BS, Gustafsson A, Thumbigere-Math V, Buhlin K. The effects of periodontal treatment on pregnancy outcomes. J Periodontol. 2013;84(4 Suppl):S195–S208. doi:https://doi.org/10.1902/jop.2013.1340014
Spivakovsky S. Periodontal treatment for the prevention of adverse birth outcomes. Evid Based Dent. 2018;19(1):12–13. doi:https://doi.org/10.1038/sj.ebd.6401286
Leon R, Silva N, Ovalle A, et al. Detection of Porphyromonas gingivalis in the amniotic fluid in pregnant women with a diagnosis of threatened premature labor. J Periodontol. 2007;78(7):1249–1255.
Ao M, Miyauchi M, Inubushi T, et al. Infection with Porphyromonas gingivalis exacerbates endothelial injury in obese mice. PLoS One. 2014;9(10):e110519.
Castro SA, Collighan R, Lambert PA, et al. Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils. Cell Death Dis. 2017;8(3):e2644.
The original online version of this article was revised due to a retrospective Open Access order.
About this article
Cite this article
Konishi, H., Urabe, S., Miyoshi, H. et al. Fetal Membrane Inflammation Induces Preterm Birth Via Toll-Like Receptor 2 in Mice With Chronic Gingivitis. Reprod. Sci. 26, 869–878 (2019). https://doi.org/10.1177/1933719118792097
- inflammation-induced preterm birth
- Porphyromonas gingivalis
- toll-like receptor-2
- uterine contractility