Toll-like Receptor 4 Mediates the Response of Epithelial and Stromal Cells to Lipopolysaccharide in the Endometrium

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2010 Sep 30

PMID 20877575

Citations 28

Authors

Iain Martin Sheldon

Mark H Roberts

Affiliations

Soon will be listed here.

Abstract

Background: Ascending 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 E(2). 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 Findings: Wild 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 E(2) 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/significance: The innate immune response to LPS in the female genital tract is dependent on TLR4 on the epithelial and stromal cells of the endometrium.

Citing Articles

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Lindsay C, Potter J, Grimshaw A, Abrahams V, Tong M Hum Reprod Update. 2023; 29(5):675-693.

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Lipid Polysaccharides have a Detrimental Effect on the Function of the Ovaries and Uterus in Mice through Increased Pro-Inflammatory Cytokines.

Seo J, Lee J, Kim S, Lee M, Yang H Dev Reprod. 2023; 26(4):135-144.

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Gene Networks and Pathways Involved in LPS-Induced Proliferative Response of Bovine Endometrial Epithelial Cells.

Najafi M, Guo Y, Andersson G, Humblot P, Bongcam-Rudloff E Genes (Basel). 2022; 13(12).

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MicroRNA Bta-miR-24-3p Suppressed Galectin-9 Expression through TLR4/NF-ĸB Signaling Pathway in LPS-Stimulated Bovine Endometrial Epithelial Cells.

Oladejo A, Li Y, Shen W, Imam B, Wu X, Yang J Cells. 2021; 10(12).

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NRF2 Exerts Anti-Inflammatory Effects in LPS-Induced gEECs by Inhibiting the Activation of the NF-B.

Bao H, Qu Q, Zhang W, Wang X, Fang J, Xue J Mediators Inflamm. 2021; 2021:9960721.

PMID: 34764818 PMC: 8577927. DOI: 10.1155/2021/9960721.

References

Hirschfeld M, Ma Y, Weis J, Vogel S, Weis J . Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J Immunol. 2000; 165(2):618-22. DOI: 10.4049/jimmunol.165.2.618. View

Young S, Lyddon T, Jorgenson R, Misfeldt M . Expression of Toll-like receptors in human endometrial epithelial cells and cell lines. Am J Reprod Immunol. 2004; 52(1):67-73. PMC: 1459423. DOI: 10.1111/j.1600-0897.2004.00189.x. View

Beutler B, Hoebe K, Du X, Ulevitch R . How we detect microbes and respond to them: the Toll-like receptors and their transducers. J Leukoc Biol. 2003; 74(4):479-85. DOI: 10.1189/jlb.0203082. View

Wang H, Dey S . Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet. 2006; 7(3):185-99. DOI: 10.1038/nrg1808. View

Sheldon I, Rycroft A, Dogan B, Craven M, Bromfield J, Chandler A . Specific strains of Escherichia coli are pathogenic for the endometrium of cattle and cause pelvic inflammatory disease in cattle and mice. PLoS One. 2010; 5(2):e9192. PMC: 2820550. DOI: 10.1371/journal.pone.0009192. View

Soboll G, Shen L, Wira C . Expression of Toll-like receptors (TLR) and responsiveness to TLR agonists by polarized mouse uterine epithelial cells in culture. Biol Reprod. 2006; 75(1):131-9. DOI: 10.1095/biolreprod.106.050690. View

Davies D, Meade K, Herath S, Eckersall P, Gonzalez D, White J . Toll-like receptor and antimicrobial peptide expression in the bovine endometrium. Reprod Biol Endocrinol. 2008; 6:53. PMC: 2627908. DOI: 10.1186/1477-7827-6-53. View

Herath S, T Lilly S, Santos N, Gilbert R, Goetze L, Bryant C . Expression of genes associated with immunity in the endometrium of cattle with disparate postpartum uterine disease and fertility. Reprod Biol Endocrinol. 2009; 7:55. PMC: 2702306. DOI: 10.1186/1477-7827-7-55. View

Herath S, T Lilly S, Fischer D, Williams E, Dobson H, Bryant C . Bacterial lipopolysaccharide induces an endocrine switch from prostaglandin F2alpha to prostaglandin E2 in bovine endometrium. Endocrinology. 2008; 150(4):1912-20. PMC: 2706387. DOI: 10.1210/en.2008-1379. View

10.

Soboll G, Crane-Godreau M, Lyimo M, Wira C . Effect of oestradiol on PAMP-mediated CCL20/MIP-3 alpha production by mouse uterine epithelial cells in culture. Immunology. 2006; 118(2):185-94. PMC: 1782293. DOI: 10.1111/j.1365-2567.2006.02353.x. View

11.

Grant K, Wira C . Effect of mouse uterine stromal cells on epithelial cell transepithelial resistance (TER) and TNFalpha and TGFbeta release in culture. Biol Reprod. 2003; 69(3):1091-8. DOI: 10.1095/biolreprod.103.015495. View

12.

Poyser N . Effects of various factors on prostaglandin synthesis by the guinea-pig uterus. J Reprod Fertil. 1987; 81(1):269-76. DOI: 10.1530/jrf.0.0810269. View

13.

Poltorak A, He X, Smirnova I, Liu M, Van Huffel C, Du X . Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998; 282(5396):2085-8. DOI: 10.1126/science.282.5396.2085. View

14.

Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y . Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol. 1999; 162(7):3749-52. View

15.

Wira C, Grant-Tschudy K, Crane-Godreau M . Epithelial cells in the female reproductive tract: a central role as sentinels of immune protection. Am J Reprod Immunol. 2005; 53(2):65-76. DOI: 10.1111/j.1600-0897.2004.00248.x. View

16.

Wira C, Fahey J, Sentman C, Pioli P, Shen L . Innate and adaptive immunity in female genital tract: cellular responses and interactions. Immunol Rev. 2005; 206:306-35. DOI: 10.1111/j.0105-2896.2005.00287.x. View

17.

Fazeli A, Bruce C, Anumba D . Characterization of Toll-like receptors in the female reproductive tract in humans. Hum Reprod. 2005; 20(5):1372-8. DOI: 10.1093/humrep/deh775. View

18.

Aflatoonian R, Tuckerman E, Elliott S, Bruce C, Aflatoonian A, Li T . Menstrual cycle-dependent changes of Toll-like receptors in endometrium. Hum Reprod. 2006; 22(2):586-93. DOI: 10.1093/humrep/del388. View

19.

Hirata T, Osuga Y, Hirota Y, Koga K, Yoshino O, Harada M . Evidence for the presence of toll-like receptor 4 system in the human endometrium. J Clin Endocrinol Metab. 2004; 90(1):548-56. DOI: 10.1210/jc.2004-0241. View

20.

Uematsu S, Matsumoto M, Takeda K, Akira S . Lipopolysaccharide-dependent prostaglandin E(2) production is regulated by the glutathione-dependent prostaglandin E(2) synthase gene induced by the Toll-like receptor 4/MyD88/NF-IL6 pathway. J Immunol. 2002; 168(11):5811-6. DOI: 10.4049/jimmunol.168.11.5811. View