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Caspase-1 Regulates Escherichia coli Sepsis and Splenic B Cell Apoptosis Independently of Interleukin-1 and Interleukin-18

Davis Heart and Lung Research Institute, The Ohio State University; and Department of Pediatrics, The Ohio State University and Columbus Children's Research Institute, Columbus, Ohio

Correspondence and requests for reprints should be addressed to Mark D. Wewers, M.D., 110L Davis Heart and Lung Research Institute, The Ohio State University, 473 West 12th Avenue, Columbus, OH 43210. E-mail: wewers.2{at}osu.edu

Rationale: Caspase-1 processes interleukin 1 (IL-1) and IL-18 but may also contribute to apoptosis. In this context, caspase-1 knockout mice have been shown to be protected from endotoxin-induced mortality, whereas IL-1 knockout mice are not protected.

Objectives: We therefore sought to delineate the mechanisms responsible for the differential responses between caspase-1 and IL-1 knockout mice.

Methods: Caspase-1 knockout, IL-1 knockout, and IL-1/IL-18 double knockout mice were compared with wild-type mice for survival after intraperitoneal challenge with live Escherichia coli.

Measurements and Main Results: Caspase-1 knockout animals were protected from bacterial challenge, whereas wild-type, IL-1 knockout, and IL-1/IL-18 double knockout animals were not. Wild-type animals and both IL-1 knockout and IL-1/IL-18 double knockout mice demonstrated significant splenic B lymphocyte apoptosis, which was absent in the caspase-1 knockout mice. Importantly, IL-1/IL-18 double knockout mice were protected from splenic cell apoptosis and sepsis-induced mortality by the caspase inhibitor zVAD-fmk. Furthermore, wild-type but not caspase-1 knockout splenic B lymphocytes induced peritoneal macrophages to assume an inhibitory phenotype.

Conclusion: Taken together, these findings suggest that caspase-1 is important in the host response to sepsis at least in part via its ability to regulate sepsis-induced splenic cell apoptosis.

Key Words: apoptosis • caspase inhibition • septic shock • spleen

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