Bacterially-induced preterm labor and regulation of prostaglandin-metabolizing enzyme expression in mice: the role of toll-like receptor 4

Biol Reprod. 2003 Dec;69(6):1957-63. doi: 10.1095/biolreprod.103.019620. Epub 2003 Aug 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Enzymes / genetics*
  • Enzymes / metabolism
  • Escherichia coli / pathogenicity*
  • Female
  • Fetus / enzymology
  • Gene Expression Regulation, Enzymologic
  • Hydroxyprostaglandin Dehydrogenases / genetics
  • Hydroxyprostaglandin Dehydrogenases / metabolism
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Membrane Glycoproteins / physiology*
  • Membrane Proteins
  • Mice
  • Mice, Inbred C3H
  • Mice, Mutant Strains
  • Obstetric Labor, Premature / enzymology*
  • Obstetric Labor, Premature / microbiology*
  • Pregnancy
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Prostaglandins / metabolism
  • Receptors, Cell Surface / physiology*
  • Toll-Like Receptor 4
  • Toll-Like Receptors


  • Enzymes
  • Isoenzymes
  • Membrane Glycoproteins
  • Membrane Proteins
  • Prostaglandins
  • Receptors, Cell Surface
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Hydroxyprostaglandin Dehydrogenases
  • 15-hydroxyprostaglandin dehydrogenase
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, mouse