title: IL-24 sensitizes tumor cells to TLR3-mediated apoptosis.
abstract: Interleukin-24 (IL-24), a member of the IL-10 cytokine family whose physiological function remains largely unknown, has been shown to induce apoptosis when expressed in an adenoviral background. It is yet little understood, why IL-24 alone induced apoptosis only in a limited number of tumor cell lines. Analyzing an influenza A virus vector expressing IL-24 for its oncolytic potential revealed enhanced pro-apoptotic activity of the chimeric virus compared with virus or IL-24 alone. Interestingly, IL-24-mediated enhancement of influenza-A-induced apoptosis did not require viral replication but critically depended on toll-like receptor 3 (TLR3) and caspase-8. Immunoprecipitation of TLR3 showed that infection by influenza A virus induced formation of a TLR3-associated signaling complex containing TRIF, RIP1, FADD, cFLIP and pro-caspase-8. Co-administration of IL-24 decreased the presence of cFLIP in the TLR3-associated complex, converting it into an atypical, TLR3-associated death-inducing signaling complex (TLR3 DISC) that induced apoptosis by enabling caspase-8 activation at this complex. The sensitizing effect of IL-24 on TLR3-induced apoptosis, mediated by influenza A virus or the TLR3-specific agonist poly(I:C), was also evident on tumor spheroids. In conclusion, rather than acting as an apoptosis inducer itself, IL-24 sensitizes cancer cells to TLR-mediated apoptosis by enabling the formation of an atypical DISC which, in the case of influenza A virus or poly(I:C), is associated with TLR3.
authors: Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria.
authors: R
authors: R
authors: Weiss
authors: M
authors: M
authors: Sachet
authors: J
authors: J
authors: Zinngrebe
authors: T
authors: T
authors: Aschacher
authors: M
authors: M
authors: Krainer
authors: B
authors: B
authors: Hegedus
authors: H
authors: H
authors: Walczak
authors: M
authors: M
authors: Bergmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000502:physiology; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D018874:Spheroids, Cellular; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D019076:Transgenes; D015854:Up-Regulation; D000099180:Interleukin-24
chemical_list: D053181:Caspase 8; D016207:Cytokines; D007378:Interleukins; D011994:Recombinant Proteins; D051196:Toll-Like Receptor 3; D000099180:Interleukin-24; C495344:TLR3 protein, human