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 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.
Laboratory for Immunological Research Schering-Plough Research Institute, Dardilly, France.
Bruno
B
Salaun
Isabelle
I
Coste
Marie-Clotilde
MC
Rissoan
Serge J
SJ
Lebecque
Toufic
T
Renno
D017209:Apoptosis / Q000276:immunology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism
D004273:DNA, Neoplasm; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; C495344:TLR3 protein, human; D048029:TNF Receptor-Associated Factor 6; D051196:Toll-Like Receptor 3; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D020169:Caspases