Pregnancy

Bacterially-Induced Preterm Labor and Regulation of Prostaglandin Metabolizing Enzyme Expression in Mice: The Role of Toll-Like Receptor 4

Abstract
Toll-like receptor 4 (TLR-4) is a critical mediator of the cellular response to lipopolysaccharide (LPS). 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 19-20 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). COX-1, COX-2, and PGDH gene expression was determined by semi-quantitative RT-PCR. 5 X 10⁹ HKE induces preterm delivery in 100% of TLR-4 normal mice, but in 0% of TLR-4 mutant mice. HKE exposure up-regulated expression of COX-2, but not 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. 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. TLR-4 may mediate bacterially induced preterm labor via regulation of prostaglandin degradation rather than its synthesis.

Key words: Pregnancy • Gene regulation • Parturition • Uterus

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