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* Department of Periodontics, School of Dental Medicine, and
Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106
Intrauterine infection plays a pivotal role in preterm birth (PTB) and is characterized by inflammation. Currently, there is no effective therapy available to treat or prevent bacterial-induced PTB. Using Fusobacterium nucleatum, a Gram-negative anaerobe frequently associated with PTB, as a model organism, the mechanism of intrauterine infection was investigated. Previously, it was shown that F. nucleatum induced preterm and term stillbirth in mice. Fusobacterial-induced placental infection was characterized by localized bacterial colonization, inflammation, and necrosis. In this study, F. nucleatum was shown to activate both TLR2 and TLR4 in vitro. In vivo, the fetal death rate was significantly reduced in TLR4-deficient mice (C57BL/6 TLR4–/– and C3H/HeJ (TLR4d/d)), but not in TLR2-deficient mice (C57BL/6 TLR2–/–), following F. nucleatum infection. The reduced fetal death in TLR4-deficient mice was accompanied by decreased placental necroinflammatory responses in both C57BL/6 TLR4–/– and C3H/HeJ. Decreased bacterial colonization in the placenta was observed in C3H/HeJ, but not in C57BL/6 TLR4–/–. These results suggest that inflammation, rather than the bacteria per se, was the likely cause of fetal loss. TLR2 did not appear to be critically involved, as no difference in bacterial colonization, inflammation, or necrosis was observed between C57BL/6 and C57BL/6 TLR2–/– mice. A synthetic TLR4 antagonist, TLR4A, significantly reduced fusobacterial-induced fetal death and decidual necrosis without affecting the bacterial colonization in the placentas. TLR4A had no bactericidal activity nor did it affect the birth outcome in sham-infected mice. TLR4A could have promise as an anti-inflammatory agent for the treatment or prevention of bacterial-induced preterm birth.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by the Philip Morris External Research program and National Institutes of Health Grant R01 DE 14924 (to Y.W.H.).
2 Address correspondence and reprint requests to Dr. Yiping W. Han, Department of Periodontics School of Dental Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106. E-mail address: yiping.han{at}case.edu
3 Abbreviations used in this paper: PTB, preterm birth; AF, amniotic fluid; hTLR, human TLR; Pam3CSK4, N-palmitoyl(S)-[2,3-bis(palmitoyloxy)-(2, RS)-propyl]- Cys-Ser-Lys4.
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