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Expression and Function of Toll-Like Receptor 4 in the Endometrial Cells of the Uterus

Royal Veterinary College, Departments of Veterinary Clinical Sciences (S.H., D.P.F., E.J.W., S.T.L., I.M.S.) and Pathology and Infectious Diseases (D.W.), University of London, North Mymms, Hatfield, Hertfordshire AL9 7TA, United Kingdom; Department of Veterinary Clinical Science and Animal Husbandry (H.D.), Faculty of Veterinary Science, University of Liverpool, Leahurst, Neston CH64 7TE, United Kingdom; and Centre for Veterinary Science (C.E.B.), Department of Clinical Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, United Kingdom

Address all correspondence and requests for reprints to Prof. Martin Sheldon, Royal Veterinary College, Department of Veterinary Clinical Sciences, University of London, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, United Kingdom. E-mail: sheldon{at}rvc.ac.uk.

Prostaglandins have a central role in many endocrine functions in mammals, including regulation of the life span of the corpus luteum by prostaglandin F₂ (PGF) and prostaglandin E₂ (PGE), which are secreted by the uterine endometrium. However, the uterus is readily infected with bacteria such as Escherichia coli, which disrupt luteolysis. Immune cells detect E. coli by Toll-like receptor 4 (TLR4) binding its pathogenic ligand, lipopolysaccharide (LPS), although signaling requires accessory molecules such as CD14. The objective of this study was to determine the effect of E. coli or LPS on the function of bovine endometrial cells, and whether purified populations of epithelial and stromal cells express the molecules involved in LPS recognition. In addition, because the female sex hormones estradiol and progesterone modify the risk of uterine infection, their effect on the LPS response was investigated. Endometrial explants produced prostaglandins in response to LPS, with an increased ratio of PGE to PGF. Addition of LPS or E. coli to stromal and epithelial cells stimulated production of PGE and PGF and increased their cyclooxygenase 2 mRNA expression. The production of prostaglandins was abrogated by an LPS antagonist. In addition, estradiol and progesterone inhibited the production of PGE and PGF in response to LPS, indicating a role for steroid hormones in the response to bacterial infection. For the first time, Toll-like receptor 4 mRNA and CD14 mRNA and protein were detected in bovine endometrial stromal and epithelial cells by RT-PCR and flow cytometry. In conclusion, epithelial and stromal cells detect and respond to bacteria, which modulate their endocrine function.

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