Bacterially-Induced Preterm Labor and Regulation of Prostaglandin-Metabolizing Enzyme Expression in Mice: The Role of Toll-Like Receptor 41

Abstract

Toll-like receptor 4 (TLR-4) is a critical mediator of the cellular response to lipopolysaccharide. Our purpose was to examine the role of TLR-4 in parturition and in the regulation of expression of prostaglandin synthase (cyclooxygenase [COX]-1 and COX-2) and 15-hydroxyprostaglandin dehydrogenase (PGDH) following exposure to heat-killed Escherichia coli (HKE) in pregnant mice. Inbred TLR-4-mutant C3H/HeJ mice and inbred normal C3HeB/FeJ mice on Day 14.5 of a 19- to 20-day gestation received intrauterine injection of either HKE or sterile vehicle (PBS). Preterm or term delivery was recorded for these animals. Tissues (myometrium, decidual caps, placentas, fetal membranes, and fetuses) were collected after injection of sterile vehicle or 5 x 109 HKE bacteria (n = 5 mice per strain per treatment per time point). The COX-1, COX-2, and PGDH gene expression was determined by semiquantitative reverse transcription-polymerase chain reaction. We found that 5 x 109 HKE induced preterm delivery in 100% of TLR-4-normal mice but in 0% of TLR-4-mutant mice. The HKE exposure up-regulated expression of COX-2, but not of COX-1, in maternal tissues in both mouse strains. The prostaglandin-catabolizing enzyme PGDH was down-regulated in myometrium, fetal membranes, and fetuses in control mice, but no change was observed in TLR-4-mutant mice after HKE treatment. These results demonstrate that a functional TLR-4 is essential for HKE-induced preterm labor and PGDH down-regulation but is not essential for HKE-induced COX-2 gene up-regulation. The TLR-4 may mediate bacterially induced preterm labor via regulation of prostaglandin degradation rather than prostaglandin synthesis.

Impact of toll-like receptor 4 deficiency on the response to uterine ischemia/reperfusion in mice

“…Heat-killed E. coli is rich in LPS, an important exogenous ligand for TLR4. LPS, at a relatively high dose, induces premature birth, but only in TLR4-competent mice (Wang & Hirsch 2003). In contrast, when LPS is given below this level, it causes not premature birth but FGR (Xu et al 2005).…”

Endocrine immune interactions in human parturition

“…Pulmonary derived surfactant proteins and phospholipids may be key to this: as the fetus matures, increased quantities are produced and so levels increase in the amniotic fluid. These surfactant proteins may well contribute to the inflammatory response that can be observed in the fetal membranes and in the underlying cervix and myometrium (Smith, 2007) given that they stimulate COX-2 activity via TLR-4 in mice (Wang and Hirsch, 2003) and subsequent prostaglandin E2 (PGE2) production in the amnion. Increased PGE2 production in the amnion could diffuse through the chorion and decidua to stimulate myometrial cell prostaglandin production and hence contractility (Slater et al, 1999, Smith, 2007.…”

The role of nuclear factor kappa B in human labour

“…They share considerable homology with the IL-1 receptors and also signal to NF-kB through the canonical pathway. Studies using Tlr-4 -/-mutant mice suggest that this TLR is a critical factor in bacterially-induced preterm labour (Wang & Hirsch 2003). Furthermore, both maternal and fetal polymorphisms of the human TLR-4 gene have been associated with spontaneous preterm labour (Varner & Esplin 2005).…”