Caspase-8 prevents sustained activation of NF-kappaB in monocytes undergoing macrophagic differentiation

Caspases have demonstrated several non-apoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral blood monocytes into macrophages. Upon Macrophage Colony Stimulating Factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-Associated Death Domain (FADD), the serine/threonine kinase Receptor-Interacting-Protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase-8 cleaves RIP1, which prevents sustained NF-κB activation, and activates downstream caspases. Altogether, these data identify a role for caspase-8 in monocytes undergoing macrophagic differentiation, i.e. the enzyme activated in an atypical complex down-regulates NF-κB activity through RIP1 cleavage.