Activation of Toll-like Receptors 2 or 3 and Preterm Delivery in the Mouse

Abstract

The objective of this study is to test whether the activation of toll-like receptors (TLRs) 2 and 3 (innate immune receptors for gram-positive and viral pathogens, respectively) can induce preterm delivery. One uterine horn of preterm pregnant CD-1 mice at approximately 75% of gestation was injected with TLR-2 ligands (lipoteichoic acid [LTA] or peptidoglycan [PGN]) or the TLR-3 ligand polyinosinic:cytidylic acid (poly[I:C]). Preterm delivery was recorded. In a separate group of mice, tissue mRNAs were quantified by reverse transcriptase polymerase chain reaction 5 hours after treatment with PGN or poly(I:C). Intrauterine PGN and LTA induced preterm delivery, reaching 100% at maximal doses. Intraperitoneal PGN also induced preterm delivery but at lower rates (maximum = 55%). Intrauterine poly(I:C) induced preterm birth in up to 31% of mice. Poly(I:C) induced uterine interferon beta and chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES) but not interleukin 1beta, tumor necrosis factor, or lipopolysaccharide-induced CXC chemokine. PGN did not alter these mRNAs when compared with saline. Neither treatment induced gene expression in fetal membranes. Activation of either TLR-2 or -3 can induce preterm delivery in the mouse. Activation of TLR-3 with poly(I:C) induces interferon beta and the chemokine CCL5 in uterine tissues but not in fetal membranes.

Innate immunity and disorders of the female reproductive tract

“…In this study, TLR4 stimulation reduced prostaglandin dehydrogenase expression in fetal membranes and myometrium resulting in increased local concentrations of prostaglandins; mediators with a well-established role in the onset of labour (Wang & Hirsch 2003). Preterm delivery also occurs in mice upon activation of TLR2 or TLR3 (Ilievski et al 2007) with TLR3 activation resulting in increased levels of CCL5 and IFNg in uterine tissues. Zhang et al (2007) have reported pregnancy failure and abnormal uterine spiral artery development in mice as a result of administration of the TLR3 agonist, poly I:C, earlier in gestation.…”

“…Fallopian tube epithelium) in the response to chlamydial infection, or any STI, remains poorly understood. However, the TLR4 normal mice treated with heat-killed Escherichia coli deliver preterm while there is no effect on TLR4 mutant mice (Wang & Hirsch 2003) Elafin mRNA and protein is [ in fetal membranes from women with preterm labour associated with chorioamnionitis (Tromp et al 2004) Activation of TLR2 or TLR3 also causes preterm labour in mice (Ilievski et al 2007) SLPI concentrations in amniotic fluid are Y in cases of preterm premature rupture of membranes TLR2 expression is Y in placentae (Rindsjo et al 2007) aforementioned differences in the expression pattern of the TLRs in individual reproductive tract microenvironments suggest they may contribute, at least in part, to a compartmentalized immune response towards pathogen invasion (Pioli et al 2004). Furthermore, a recent study examining single nucleotide polymorphisms in TLR9, TLR4, CD14 and NOD2 in women with chlamydial infections indicated that women with SNPs in two or more of these genes have a trend towards an increased risk of tubal pathology (den Hartog et al 2006) suggesting that pattern recognition receptors are involved in the progression of the infection.…”

TLR6 Modulates First Trimester Trophoblast Responses to Peptidoglycan

“…Recently, Ilievski et al (42) reported that i.p. administration of high doses of PDG to wild-type animals late in gestation induces preterm delivery.…”

“…Furthermore, PDG and LTA are known to trigger prematurity in vivo (41,42). Therefore, the aims of this study were to determine whether PDG-induced pregnancy complications are associated with excessive placental apoptosis and to characterize the cellular mechanism by which TLR2 mediates PDG-induced apoptosis in first trimester trophoblast cells.…”

Risks associated with viral infections during pregnancy

“…Initial studies consisted of administration of TLR ligands, such as Poly(I:C), to pregnant WT or Tlr3-KO mice to mimic viral signaling during pregnancy (71,72). This induced preterm labor in WT but not Tlr3-…”