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Insulin-dependent PI3-Kinase/Akt and ERK signaling pathways inhibit TLR3-mediated HBEC apoptosis

Takanori Numata, Jun Araya, Satoko Fujii, Hiromichi Hara, Naoki Takasaka, Yoko Yumino, Makoto Kawaishi, Jun Hirano, Makoto Odaka, Toshiaki Morikawa, Katsutoshi Nakayama, Kazuyoshi Kuwano
European Respiratory Journal 2011 38: p429; DOI:
Takanori Numata
1Department of Internal Medicine, Division of Respiratory Diseases, Jikei University School of Medicine, Tokyo, Japan
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Jun Araya
1Department of Internal Medicine, Division of Respiratory Diseases, Jikei University School of Medicine, Tokyo, Japan
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Satoko Fujii
1Department of Internal Medicine, Division of Respiratory Diseases, Jikei University School of Medicine, Tokyo, Japan
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Hiromichi Hara
1Department of Internal Medicine, Division of Respiratory Diseases, Jikei University School of Medicine, Tokyo, Japan
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Naoki Takasaka
1Department of Internal Medicine, Division of Respiratory Diseases, Jikei University School of Medicine, Tokyo, Japan
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Yoko Yumino
1Department of Internal Medicine, Division of Respiratory Diseases, Jikei University School of Medicine, Tokyo, Japan
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Makoto Kawaishi
1Department of Internal Medicine, Division of Respiratory Diseases, Jikei University School of Medicine, Tokyo, Japan
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Jun Hirano
2Division of Chest Surgery, Jikei University School of Medicine, Tokyo, Japan
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Makoto Odaka
2Division of Chest Surgery, Jikei University School of Medicine, Tokyo, Japan
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Toshiaki Morikawa
2Division of Chest Surgery, Jikei University School of Medicine, Tokyo, Japan
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Katsutoshi Nakayama
1Department of Internal Medicine, Division of Respiratory Diseases, Jikei University School of Medicine, Tokyo, Japan
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Kazuyoshi Kuwano
1Department of Internal Medicine, Division of Respiratory Diseases, Jikei University School of Medicine, Tokyo, Japan
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Abstract

Introduction: TLR 3 mainly recognizes viral-associated dsRNA. However, recognition of dsRNA byproducts released from apoptotic and necrotic cells is a recently proposed mechanism for the amplification of virulence, suggesting a pivotal participation of TLR3 not only in viral infection, but also in lung diseases where apoptosis plays a critical role, such as asthma and COPD. In addition to metabolic control, insulin signaling has also been postulated to be protective by inhibiting apoptosis.

Aims: We explored the role of insulin signaling in protecting human bronchial epithelial cells (HBEC) against TLR3-mediated apoptosis.

Methods: For the experiments of apoptosis induction by polyinosinic-polycytidylic acid (poly (I:C)), a dsRNA analog, HBEC and airway fragments were treated in the presence or absence of insulin. Knock down of TLR3 was performed by siRNA transfection. Wortmannin (PI3-kinase inhibitor) and PD98059 (MEK inhibitor) were used to elucidate the role of insulin-dependent signaling pathways.

Results: Significant TLR3-mediated apoptosis was induced by poly (I:C), via caspase-8-dependent mechanisms. However, insulin efficiently inhibited TLR3/poly (I:C) induced HBEC apoptosis via PI3-kinase/Akt and ERK pathways, at least partly via the up-regulation of cellular FLICE-inhibitory proteins (cFLIPs) and additionally through protein synthesis-independent mechanisms.

Conclusions: These results implicate TLR3-mediated dsRNA-induced apoptosis in apoptosis-driven lung disease pathogenesis and provide evidence for a novel protective role of insulin.

  • © 2011 ERS
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Insulin-dependent PI3-Kinase/Akt and ERK signaling pathways inhibit TLR3-mediated HBEC apoptosis
Takanori Numata, Jun Araya, Satoko Fujii, Hiromichi Hara, Naoki Takasaka, Yoko Yumino, Makoto Kawaishi, Jun Hirano, Makoto Odaka, Toshiaki Morikawa, Katsutoshi Nakayama, Kazuyoshi Kuwano
European Respiratory Journal Sep 2011, 38 (Suppl 55) p429;

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Insulin-dependent PI3-Kinase/Akt and ERK signaling pathways inhibit TLR3-mediated HBEC apoptosis
Takanori Numata, Jun Araya, Satoko Fujii, Hiromichi Hara, Naoki Takasaka, Yoko Yumino, Makoto Kawaishi, Jun Hirano, Makoto Odaka, Toshiaki Morikawa, Katsutoshi Nakayama, Kazuyoshi Kuwano
European Respiratory Journal Sep 2011, 38 (Suppl 55) p429;
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