title: Insulin-dependent phosphatidylinositol 3-kinase/Akt and ERK signaling pathways inhibit TLR3-mediated human bronchial epithelial cell apoptosis.
abstract: TLR3, one of the TLRs involved in the recognition of infectious pathogens for innate and adaptive immunity, primarily recognizes viral-associated dsRNA. Recognition of dsRNA byproducts released from apoptotic and necrotic cells is a recently proposed mechanism for the amplification of toxicity, suggesting a pivotal participation of TLR3 in viral infection, as well as in lung diseases where apoptosis plays a critical role, such as asthma and chronic obstructive pulmonary disease. In addition to metabolic control, insulin signaling was postulated to be protective by inhibiting apoptosis. Therefore, we explored the role of insulin signaling in protecting against TLR3-mediated apoptosis of human bronchial epithelial cells. Significant TLR3-mediated apoptosis was induced by polyinosinic-polycytidylic acid, a dsRNA analog, via caspase-8-dependent mechanisms. However, insulin efficiently inhibited TLR3/polyinosinic-polycytidylic acid-induced human bronchial epithelial cell apoptosis via PI3K/Akt and ERK pathways, at least in part, via upregulation of cellular FLIPs and through protein synthesis-independent mechanisms. These results indicate the significance of TLR3-mediated dsRNA-induced apoptosis in the pathogenesis of apoptosis-driven lung disease and provide evidence for a novel protective role of insulin.
authors.affiliation: Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Numata
authors.forename: Jun
authors.initials: J
authors.lastname: Araya
authors.forename: Satoko
authors.initials: S
authors.lastname: Fujii
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Hara
authors.forename: Naoki
authors.initials: N
authors.lastname: Takasaka
authors.forename: Jun
authors.initials: J
authors.lastname: Kojima
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Minagawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yumino
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawaishi
authors.forename: Jun
authors.initials: J
authors.lastname: Hirano
authors.forename: Makoto
authors.initials: M
authors.lastname: Odaka
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Morikawa
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nishimura
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kuwano
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D001980:Bronchi / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D020545:Respiratory Mucosa / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D007328:Insulin; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases