HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Abrahams, V. M. Articles by Mor, G. PubMed PubMed Citation Articles by Abrahams, V. M. Articles by Mor, G. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Nucleotide Protein UniGene Substance via MeSH Medline Plus Health Information High Risk Pregnancy Infections and Pregnancy Uterine Diseases

TLR6 Modulates First Trimester Trophoblast Responses to Peptidoglycan¹

Vikki M. Abrahams^2,*, Paulomi B. Aldo^*, Shaun P. Murphy^,, Irene Visintin^*, Kaori Koga^*, Gabriella Wilson^*, Roberto Romero, Surendra Sharma^, and Gil Mor^2,*

^* Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520; Department of Pediatrics and Department of Pathology, Women and Infants’ Hospital, Rhode Island Hospital-Brown University, Providence, RI 02903; and Perinatology Research Branch, National Institute of Child Health and Human Development, Detroit, MI 48201

Intrauterine bacterial infections are a well-established cause of pregnancy complications. One key observation in a number of abnormal pregnancies is that placental apoptosis is significantly elevated. First trimester trophoblast cells are known to express TLR1 and TLR2 and to undergo apoptosis following exposure to Gram-positive bacterial peptidoglycan (PDG). Thus, the objectives of this study were to determine whether PDG-induced pregnancy complications are associated with placental apoptosis and to characterize the cellular mechanisms involved. We have demonstrated, using an animal model, that delivery of PDG to pregnant mice early in gestation resulted in highly elevated placental apoptosis, evidenced by trophoblast M-30 and active caspase 3 immunostaining. Using an in vitro model of human first trimester trophoblasts, apoptosis induced by PDG was found to be mediated by both TLR1 and TLR2 and that this could be blocked by the presence of TLR6. Furthermore, in the presence of TLR6, exposure to PDG resulted in trophoblast NF-B activation and triggered these cells to secrete IL-8 and IL-6. The findings of this study suggest that a Gram-positive bacterial infection, through TLR2 and TLR1, may directly promote the elevated trophoblast cell death and that this may be the underlying mechanism of pregnancy complications, such as preterm delivery. Furthermore, the expression of TLR6 may be a key factor in determining whether the response to PDG would be apoptosis or inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported in part by Grant RO1HD049446-01 from the National Institute of Child Health and Human Development (to V.M.A.), Grants P20RR018728 and P42ES013660 from National Institutes of Health and National Institute on Environmental Health Sciences (to S.S.), and the Perinatology Research Branch, Division of Intramural Research of National Institute of Child Health and Human Development.

² Address correspondence and reprint requests to Dr. Vikki M. Abrahams and Dr. Gil Mor, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520. E-mail addresses: vikki.abrahams{at}yale.edu and gil.mor{at}yale.edu

³ Abbreviations used in this paper: TIR, Toll/IL-1R homology region; LTA, lipoteichoic acid; DN, dominant negative; MOM, mouse-on-mouse; RLU, relative unit.