Roles of caspase-8 and caspase-10 in innate immune responses to double-stranded RNA.
Upon viral infection, host cells trigger antiviral immune responses by inducing type I IFN and inflammatory cytokines. dsRNA generated during viral replication is recognized by the cytoplasmic RNA helicases retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, which interact with an adaptor, IFN-beta promoter stimulator-1, to activate the transcription factors NF-kappaB and IFN regulatory factor 3. In this article we demonstrate that caspase-8 and caspase-10 are involved in these pathways. Both caspases were cleaved during dsRNA stimulation, and overexpression of a cleaved form of these caspases activated NF-kappaB. Knockdown of caspase-10 or caspase-8 in a human cell line resulted in the reduction of inflammatory cytokine production. Cells derived from caspase-8-deficient mice also showed reduced expression of inflammatory cytokines as well as NF-kappaB activation. Furthermore, the Fas-associated death domain protein interacted with these two caspases and IFN-beta promoter stimulator 1. These results indicate that caspase-8 and caspase-10 are essential components that mediate NF-kappaB-dependent inflammatory responses in antiviral signaling.
Takahashi
Ken
K
Department of Host Defense, Japan Science and Technology Agency, Research Institute for Microbial Diseases, Osaka University, Suita.
Kawai
Taro
T
Kumar
Himanshu
H
Sato
Shintaro
S
Yonehara
Shin
S
Akira
Shizuo
S
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000818:Animals; D001483:Base Sequence; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D053200:Fas-Associated Death Domain Protein; D007113:Immunity, Innate; D066298:In Vitro Techniques; D007249:Inflammation / Q000201:enzymology / Q000209:etiology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D012330:RNA, Double-Stranded; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases; C506438:CASP10 protein, human