TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells

TLRs function as molecular sensors to detect pathogen-derived products and trigger protective responses ranging from secretion of cytokines that increase the resistance of infected cells and chemokines that recruit immune cells to cell death that limits microbe spreading. Viral dsRNA participate in...

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Bibliographic Details
Published in:Journal of Immunology 2006-04, Vol.176 (8), p.4894-4901
Main Authors: Salaun, Bruno, Coste, Isabelle, Rissoan, Marie-Clotilde, Lebecque, Serge J, Renno, Toufic
Format: Article
Language:English
Subjects:
Apoptosis - immunology
Base Sequence
Breast Neoplasms - genetics
Breast Neoplasms - immunology
Breast Neoplasms - pathology
Caspases - metabolism
Cell Line, Tumor
DNA, Neoplasm - genetics
eIF-2 Kinase - metabolism
Female
Humans
Interferon Type I - metabolism
Interleukin-1 Receptor-Associated Kinases
Intracellular Signaling Peptides and Proteins - metabolism
NF-kappa B - metabolism
Protein-Serine-Threonine Kinases - metabolism
RNA, Small Interfering - genetics
Signal Transduction
TNF Receptor-Associated Factor 6 - metabolism
Toll-Like Receptor 3 - agonists
Toll-Like Receptor 3 - genetics
Toll-Like Receptor 3 - metabolism
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Summary:TLRs function as molecular sensors to detect pathogen-derived products and trigger protective responses ranging from secretion of cytokines that increase the resistance of infected cells and chemokines that recruit immune cells to cell death that limits microbe spreading. Viral dsRNA participate in virus-infected cell apoptosis, but the signaling pathway involved remains unclear. In this study we show that synthetic dsRNA induces apoptosis of human breast cancer cells in a TLR3-dependent manner, which involves the molecular adaptor Toll/IL-1R domain-containing adapter inducing IFN-beta and type I IFN autocrine signaling, but occurs independently of the dsRNA-activated kinase. Moreover, detailed molecular analysis of dsRNA-induced cell death established the proapoptotic role of IL-1R-associated kinase-4 and NF-kappaB downstream of TLR3 as well as the activation of the extrinsic caspases. The direct proapoptotic activity of endogenous human TLR3 expressed by cancerous cells reveals a novel aspect of the multiple-faced TLR biology, which may open new clinical prospects for using TLR3 agonists as cytotoxic agents in selected cancers.
ISSN:0022-1767
1550-6606
1365-2567
DOI:10.4049/jimmunol.176.8.4894