Cutting edge: 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-in-ducible gene I and melanoma differentiation-associated gene 5, which interact with an adaptor, IFN-beta promoter stimulator-1, to activate the transcription factors NF-kappa B 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-kappa B. Knockdown of caspase-10 or caspase-8 in a human cell line resulted in the reduction of inflammatory cytokine production. CA derived from caspase-8-deficient mice also showed reduced expression Of inflammatory cytokines as well as NF-kappa B 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 andcaspase-10 are essential components that mediate NF-kappa B-dependent inflammatory responses in antiviral signaling.