1. Department of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA
2. Department of Immunology, The Scripps Research Institute, San Diego, California 92037, USA
3. Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA
4. †Present addresses: Department of Medicine, McGill University, Montreal H3A 1A1, Canada (M.S.); Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA (D.R.G.)
5. *These authors contributed equally to this work

Correspondence to: Douglas R. Green^1,5,4Donald W. Nicholson^5,3 Correspondence and requests for materials should be addressed to D.W.N (Email: donald_nicholson@merck.com) or D.R.G. (Email: douglas.green@stjude.org).

Abstract

Caspases function in both apoptosis and inflammatory cytokine processing and thereby have a role in resistance to sepsis¹. 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)-1, IL-18 (interferon (IFN)- inducing factor) and IFN-, but not tumour-necrosis factor- and IL-6, in response to various bacterial components that stimulate Toll-like receptor and NOD pathways. The IFN- pathway was crucial in mediating survival of septic caspase-12-deficient mice, because administration of neutralizing antibodies to IFN- 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-1 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.

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