title: Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C).
abstract: The objective of this study was to examine the expression of TLR by human primary uterine epithelial cells (UEC) and to determine whether exposure to the TLR agonist poly(I:C) would induce an antiviral response. The secretion of several cytokines and chemokines was examined as well as the mRNA expression of human beta-defensin-1 and -2 (HBD1 and HBD2), IFN-beta, and the IFN-beta-stimulated genes myxovirus resistance gene 1 and 2',5' oligoadenylate synthetase. The expression of TLR1-9 by UEC was demonstrated by RT-PCR, with only TLR10 not expressed. Stimulation of UEC with the TLR3 agonist poly(I:C) induced the expression of the proinflammatory cytokines TNF-alpha, IL-6, GM-CSF, and G-CSF, as well as the chemokines CXCL8/IL-8, CCL2/MCP-1, and CCL4/MIP-1beta. In addition, poly(I:C) exposure induced the mRNA expression of HBD1 and HBD2 by 6- and 4-fold, respectively. Furthermore, upon exposure to poly(I:C) UEC initiated a potent antiviral response resulting in the induction of IFN-beta mRNA expression 70-fold and myxovirus resistance gene 1 and 2',5' oligoadenylate synthetase mRNA expression (107- and 96-fold), respectively. These results suggest that epithelial cells that line the uterine cavity are sensitive to viral infection and/or exposure to viral dsRNA released from killed epithelial cells. Not only do UEC release proinflammatory cytokines and chemokines that mediate the initiation of an inflammatory response and recruitment of immune cells to the site of infection, but they also express beta-defensins, IFN-beta, and IFN-beta-stimulated genes that can have a direct inhibiting effect on viral replication.
authors.affiliation: Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756, USA. todd.m.schaefer@dartmouth.edu
authors.forename: Todd M
authors.initials: TM
authors.lastname: Schaefer
authors.forename: John V
authors.initials: JV
authors.lastname: Fahey
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Wright
authors.forename: Charles R
authors.initials: CR
authors.lastname: Wira
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054407:Chemokine CCL4; D018925:Chemokines / Q000378:metabolism; D019742:Chemokines, CC; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000096:biosynthesis / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000096:biosynthesis / Q000276:immunology; D051194:Toll-Like Receptor 1; D051201:Toll-Like Receptor 10; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D014599:Uterus / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D023083:beta-Defensins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; C066507:CCL4 protein, human; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; C406407:DEFB1 protein, human; C106641:DEFB4A protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495344:TLR3 protein, human; D051194:Toll-Like Receptor 1; D051201:Toll-Like Receptor 10; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D016179:Granulocyte Colony-Stimulating Factor; D016899:Interferon-beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011070:Poly I-C