@article {309734, title = {Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice.}, journal = {Nature}, volume = {440}, year = {2006}, month = {2006 Apr 20}, pages = {1064-8}, abstract = {

Caspases function in both apoptosis and inflammatory cytokine processing and thereby have a role in resistance to sepsis. Here we describe a novel role for a caspase in dampening responses to bacterial infection. We show that in mice, gene-targeted deletion of caspase-12 renders animals resistant to peritonitis and septic shock. The resulting survival advantage was conferred by the ability of the caspase-12-deficient mice to clear bacterial infection more efficiently than wild-type littermates. Caspase-12 dampened the production of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-18 (interferon (IFN)-gamma inducing factor) and IFN-gamma, but not tumour-necrosis factor-alpha and IL-6, in response to various bacterial components that stimulate Toll-like receptor and NOD pathways. The IFN-gamma pathway was crucial in mediating survival of septic caspase-12-deficient mice, because administration of neutralizing antibodies to IFN-gamma receptors ablated the survival advantage that otherwise occurred in these animals. Mechanistically, caspase-12 associated with caspase-1 and inhibited its activity. Notably, the protease function of caspase-12 was not necessary for this effect, as the catalytically inactive caspase-12 mutant Cys299Ala also inhibited caspase-1 and IL-1beta production to the same extent as wild-type caspase-12. In this regard, caspase-12 seems to be the cFLIP counterpart for regulating the inflammatory branch of the caspase cascade. In mice, caspase-12 deficiency confers resistance to sepsis and its presence exerts a dominant-negative suppressive effect on caspase-1, resulting in enhanced vulnerability to bacterial infection and septic mortality.

}, keywords = {Animals, Caspase 1, Caspase 12, Caspase Inhibitors, Caspases, Catalysis, Cell Line, Disease Susceptibility, Humans, Interferon-gamma, Interleukin-1, Interleukin-18, Listeria monocytogenes, Mice, Mice, Knockout, Mutation, Peritonitis, Protein Binding, Sepsis, Shock, Septic, Survival Rate}, issn = {1476-4687}, doi = {10.1038/nature04656}, author = {Saleh, Maya and Mathison, John C and Wolinski, Melissa K and Bensinger, Steve J and Fitzgerald, Patrick and Droin, Nathalie and Ulevitch, Richard J and Green, Douglas R and Nicholson, Donald W} }