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* Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520;
King’s College London, London, United Kingdom; and
Department of Obstetrics and Gynecology, University of Pretoria, Pretoria, South Africa
TLRs are pattern recognition transmembrane receptors that play key roles in innate immunity. A recently discovered soluble truncated form of TLR2 (sTLR2) acts as a decoy receptor, down-regulating the host inflammatory response to bacteria. To identify the presence and functional role of sTLR2 in modulating the intraamniotic inflammatory response to infection, we studied 109 amniotic fluid samples of women with normal pregnancy outcomes (n = 28) and women with (n = 39) and without (n = 42) intraamniotic infection. We sought to demonstrate a functional role of the amniotic fluid sTLR2 in modulating the TLR2 inflammatory signaling in vitro by using a villous explant system. Two sTLR2 forms were identified, and specificity was confirmed with neutralizing peptides. We showed that sTLR2 is present constitutively in amniotic fluid, its levels are gestational age dependent, and we determined that the sTLR2 quantity and functional engagement modulates the intensity of the intraamniotic inflammation elicited by Gram-positive bacteria. In vitro, we demonstrated that challenging placental villous explants with a specific TLR2 agonist (Pam3Cys) induced a significant cytokine response. Notably, preincubation of the preterm, but not near-term, amniotic fluid with Pam3Cys significantly inhibited the ability of this TLR2 agonist to elicit a cytokine reaction. Moreover, depletion of sTLR2 from preterm amniotic fluid removed its neutralizing property. Monensin significantly diminished sTLR2 immunoreactivity, indicating that sTLR2 is the result of intracellular posttranslational processing of TLR2. We conclude that sTLR2 is part of the amniotic fluid innate immune system and participates in regulating the inflammatory response to microbial pathogens.
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1 This work was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grant RO1 HD 047321-01 (to I.A.B.) and departmental funds. The funding sources had no involvement in study design, interpretation of data, writing of the report or decision to submit the paper for publication.
A.T.D. and I.A.B. designed the study, performed the experiments, collected, analyzed, and interpreted the clinical and experimental data, and drafted the manuscript. C.S.B. participated in the study design, supervised the clinical enrollment of the patients, collected, analyzed, and interpreted the clinical and experimental data, and participated with A.T.D. and I.A.B. in writing the manuscript. G.Z. conducted the ELISA assays, performed part of the experiments, and participated in writing of the report. S.J. assisted with experiments and data interpretation and participated in writing of the report. E.O. and A.B. participated with aspects of the study design, performance of the experiments, and participated in writing of the report. All listed authors have reviewed and approved the submitted version of the paper.
2 Address correspondence and reprint requests to Dr. Antonette T. Dulay, Department of Obstetrics, Gynecology and Reproductive Science, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520. E-mail address: antonette.dulay{at}yale.edu
3 Abbreviations used in this paper: PAMP, pathogen-associated molecular patterns; GA, gestational age; LDH, lactate dehydrogenase; Pam3Cys, Pam3Cys-Ser-(Lys)4 hydrochloride; sTLR2, soluble TLR2.
4 The online version of this article contains supplemental material.
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