Anti-inflammatory Functions of Caspase-8

Abstract

Explorations of the functions of receptors of the TNF/NGF family have led to the discovery of various signaling proteins, many of which were later found to mediate effects of other inducers as well. We now have quite detailed knowledge of the mechanisms and molecular complexes by which some of the signaling proteins mediate these additional effects. This, however, is not the case for caspase-8. This signaling protein, which was initially identified as the proximal enzyme in the induction of apoptotic death by the death receptors, was subsequently reported to serve additional functions independently of those receptors. Whereas the mechanisms by which caspase-8 mediates cell death induction have been described in detail, almost nothing is known of the way it serves other functions. Findings that we presented at the 12th Biennial TNF Conference indicate that one of the physiological roles of this enzyme is to suppress inflammation. We further showed that one way by which caspase-8 does this is by associating with the RIG-I signaling complex and inhibiting some of the signaling mechanisms that are triggered upon formation of this complex in response to cytoplasmic ribonucleic acid. We illustrated the physiological role of caspase-8 in suppressing excessive inflammation by describing a fatal chronic skin inflammatory disease that occurs in mice as a result of deletion of caspase-8 from the epidermis.