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
