title: TLR6 modulates first trimester trophoblast responses to peptidoglycan.
abstract: 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-kappaB 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.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA. vikki.abrahams@yale.edu
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
authors.forename: Paulomi B
authors.initials: PB
authors.lastname: Aldo
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Murphy
authors.forename: Irene
authors.initials: I
authors.lastname: Visintin
authors.forename: Kaori
authors.initials: K
authors.lastname: Koga
authors.forename: Gabriella
authors.initials: G
authors.lastname: Wilson
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Surendra
authors.initials: S
authors.lastname: Sharma
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010457:Peptidoglycan / Q000276:immunology* / Q000494:pharmacology; D011247:Pregnancy / Q000276:immunology; D011251:Pregnancy Complications, Infectious / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D011261:Pregnancy Trimester, First / Q000276:immunology*; D047928:Premature Birth; D051194:Toll-Like Receptor 1 / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000096:biosynthesis / Q000276:immunology*; D014327:Trophoblasts / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D014591:Uterine Diseases / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology
chemical_list: C508606:CXCL8 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D010457:Peptidoglycan; C495342:TLR2 protein, human; C495368:TLR6 protein, human; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6