Abstract
BackgroundAscending infections of the female genital tract with bacteria causes pelvic inflammatory disease (PID), preterm labour and infertility. Lipopolysaccharide (LPS) is the main component of the cell wall of Gram-negative bacteria. Innate immunity relies on the detection of LPS by Toll-like receptor 4 (TLR4) on host cells. Binding of LPS to TLR4 on immune cells stimulates secretion of pro-inflammatory cytokines such as IL-6, chemokines such as CXCL1 and CCL20, and prostaglandin E2. The present study tested the hypothesis that TLR4 on endometrial epithelial and stromal cells is essential for the innate immune response to LPS in the female genital tract.Methodology/Principal FindingsWild type (WT) mice expressed TLR4 in the endometrium. Intrauterine infusion of purified LPS caused pelvic inflammatory disease, with accumulation of granulocytes throughout the endometrium of WT but not Tlr4−/− mice. Intra-peritoneal infusion of LPS did not cause PID in WT or Tlr4−/− mice, indicating the importance of TLR4 in the endometrium for the detection of LPS in the female genital tract. Stromal and epithelial cells isolated from the endometrium of WT but not Tlr4−/− mice, secreted IL-6, CXCL1, CCL20 and prostaglandin E2 in response to LPS, in a concentration and time dependent manner. Co-culture of combinations of stromal and epithelial cells from WT and Tlr4−/− mice provided little evidence of stromal-epithelial interactions in the response to LPS.Conclusions/SignificanceThe innate immune response to LPS in the female genital tract is dependent on TLR4 on the epithelial and stromal cells of the endometrium.
Highlights
Ascending infection of the upper female genital tract with bacteria causes pelvic inflammatory disease (PID) in women, with an influx of granulocytes such as neutrophils and macrophages into the endometrium [1]
To examine if Toll-like receptor 4 (TLR4) is necessary for the detection of LPS in the endometrium, Wild type (WT) and Tlr42/2 mice were infused intrauterine with 100 ml of vehicle or 100 mg ultrapure LPS from E. coli O111:B4
The number of cells did not differ significantly between the WT mice infused with vehicle and the Tlr42/2 mice infused with vehicle or LPS (Fig. 3A)
Summary
Ascending infection of the upper female genital tract with bacteria causes pelvic inflammatory disease (PID) in women, with an influx of granulocytes such as neutrophils and macrophages into the endometrium [1]. Lipopolysaccharide (LPS) is the major structural component of the cell wall of Gram-negative bacteria but is the endotoxin responsible for much of the inflammation and shock associated with bacterial infection [6]. Ascending infections of the female genital tract with bacteria causes pelvic inflammatory disease (PID), preterm labour and infertility. Binding of LPS to TLR4 on immune cells stimulates secretion of pro-inflammatory cytokines such as IL-6, chemokines such as CXCL1 and CCL20, and prostaglandin E2. The present study tested the hypothesis that TLR4 on endometrial epithelial and stromal cells is essential for the innate immune response to LPS in the female genital tract
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