Caspase-1 regulates Escherichia coli sepsis and splenic B cell apoptosis independently of interleukin-1β and interleukin-18

Rationale: Caspase-1 processes interleukin 1 beta (IL-1 beta) 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 beta knockout mice are not protected. Objectives: We therefore sought to delineate the mechanisms responsible for the differential responses between caspase-1 and IL-1 beta knockout mice. Methods: Caspase-1 knockout, IL-1 beta knockout, and IL-1 beta/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, ILAP knockout, and IL-1 beta/IL-18 double knockout animals were not. Wild-type animals and both ILAP knockout and IL-1 beta/IL-18 double knockout mice demonstrated significant splenic B lymphocyte apoptosis, which was absent in the caspase-1 knockout mice. Importantly, IL-1 beta/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.