title: Polyinosinic-Polycytidylic Acid Perturbs Ovarian Functions Through Toll-Like Receptor 3-Mediated Tumor Necrosis Factor A Production in Female Mice.
abstract: Viral infections may perturb ovarian functions and female fertility. Mechanisms underlying viral perturbation of ovarian functions are incompletely understood. This study found that intraperitoneal injection of polyinosinic-polycytidylic acid [poly (I:C)] in female mice inhibits estradiol synthesis and induces ovarian granulosa cell apoptosis. Poly (I:C) is a synthetic viral double-stranded RNA analog, which induces innate antiviral responses mimicking a viral infection through activation of pattern recognition receptors, including toll-like receptor 3 (TLR3), retinoic acid-inducible gene I, and melanoma differentiation-associated gene 5. Injection of poly (I:C) significantly induced granulosa cell apoptosis in antral follicles and reduced antral follicle numbers. These effects were significantly diminished in Tlr3 knockout or tumor necrosis factor-alpha (Tnfa) knockout mice. We demonstrated that poly (I:C) induced TNFA production at a relatively high level in wild-type mice compared with that in Tlr3 knockout mice. Notably, TNFA neutralizing antibody significantly reduced poly (I:C)-induced ovarian dysfunction. In vitro assays confirmed that TNFA inhibits estradiol synthesis and induces granulosa cell apoptosis. Results provide novel insights into the mechanisms by which a mimicked viral infection perturbs ovarian functions in mice.
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Keqin
authors.initials: K
authors.lastname: Yan
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Lijing
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Shutao
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Han
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China dshan@ibms.pumc.edu.cn.
authors.forename: Daishu
authors.initials: D
authors.lastname: Han
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; D011070:Poly I-C
keywords: TNFA; ovary; toll-like receptor 3; viral infection