RT Journal Article
SR Electronic
T1 Insulin-dependent PI3-Kinase/Akt and ERK signaling pathways inhibit TLR3-mediated HBEC apoptosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP p429
VO 38
IS Suppl 55
A1 Takanori Numata
A1 Jun Araya
A1 Satoko Fujii
A1 Hiromichi Hara
A1 Naoki Takasaka
A1 Yoko Yumino
A1 Makoto Kawaishi
A1 Jun Hirano
A1 Makoto Odaka
A1 Toshiaki Morikawa
A1 Katsutoshi Nakayama
A1 Kazuyoshi Kuwano
YR 2011
UL http://erj.ersjournals.com/content/38/Suppl_55/p429.abstract
AB 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.