The Mechanism of Caspase-8-Mediated Gene Expression and Its Integral Role in Host Defense

Caspase-8 is a key integrator of cell survival and cell death decisions during infection and inflammation. Additionally, caspase-8 has an important, but less understood, role in cell-intrinsic inflammatory gene expression. Macrophages lacking caspase-8 have defective inflammatory cytokine expression in response to bacterial infection or TLR stimulation. How caspase-8 regulates cytokine gene expression, and whether caspase-8-mediated gene regulation has a physiological role during infection remains poorly defined. In this thesis we demonstrate that both caspase-8 enzymatic activity and scaffolding functions play a role in control of inflammatory cytokine gene expression. Caspase-8 enzymatic activity mediates IKK phosphorylation and nuclear translocation of the NF-κB family member c-Rel to promote maximal expression of Il1b and Il12b. Overexpression of c-Rel was sufficient to restore expression of IL-12 and IL-1β in caspase-8-deficient cells. Moreover, the cytokine regulatory function of caspase-8 promoted host survival during infection by the intracellular parasite Toxoplasma gondii. Caspase-8-deficient mice displayed acute mortality during T. gondii infection and a defect in intracellular IL-12 production by DCs. Exogenous IL-12 promoted complete survival of caspase-8-deficient mice during acute toxoplasmosis. Our findings provide new insight into how caspase-8 controls inflammatory gene expression and, for the first time, identify a critical role for caspase-8 in host defense against a eukaryotic pathogen