title: Divergent trophoblast responses to bacterial products mediated by TLRs.
abstract: Intrauterine infections have been associated with pregnancy complications that are also linked with increased trophoblast apoptosis. TLRs are key components of the innate immune system which recognize conserved sequences on the surface of pathogens and trigger effector cell functions. We hypothesize that intrauterine infections may cause the excessive trophoblast cell apoptosis observed in abnormal pregnancies and that TLR may provide a mechanism of pathogenesis. In this study we describe the expression and function of TLR-2 and TLR-4 in first trimester trophoblast cells. Although ligation of TLR4 induced cytokine production by trophoblast cells, TLR-2 activation induced apoptosis. TLR-2 mediated apoptosis was dependent upon the Fas-associated death domain, the inactivation of the X-linked inhibitor of apoptosis, and the activation of caspases 8, 9, and 3. These results suggest that certain intrauterine infections may directly induce trophoblast cell death through TLR-2. Our findings provide a novel mechanism of pathogenesis for certain pregnancy complications in which there is engagement of the innate immune system.
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
authors.forename: Paulomi
authors.initials: P
authors.lastname: Bole-Aldo
authors.forename: Yeon Mee
authors.initials: YM
authors.lastname: Kim
authors.forename: Shawn L
authors.initials: SL
authors.lastname: Straszewski-Chavez
authors.forename: Tinnakorn
authors.initials: T
authors.lastname: Chaiworapongsa
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000276:immunology; D001412:Bacillus subtilis / Q000276:immunology*; D002352:Carrier Proteins / Q000502:physiology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology*; D053200:Fas-Associated Death Domain Protein; D005260:Female; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000276:immunology / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D013211:Staphylococcus aureus / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection; D014327:Trophoblasts / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology*; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D016207:Cytokines; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D006131:Growth Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; D011506:Proteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019014:fas Receptor; D020169:Caspases