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Published ahead of print on August 14, 2006, doi:10.1164/rccm.200604-546OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 9, November 2006, 1003-1010

A more recent version of this article appeared on November 1, 2006
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Submitted on April 20, 2006
Accepted on August 10, 2006

Caspase-1 Regulates E. coli Sepsis and Splenic B Cell Apoptosis Independently of IL-1{beta} and IL-18

Anasuya Sarkar1, Mark W Hall2, Matthew Exline1, Judith Hart1, Nina Knatz3, Na Tosha Gatson1, and Mark D Wewers1*

1 Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA, 2 Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Pediatrics, The Ohio State University and Columbus Children's Research Institute, Columbus, OH, USA, 3 Department of Pediatrics, The Ohio State University and Columbus Children's Research Institute, Columbus, OH, USA

* To whom correspondence should be addressed. E-mail: wewers.2{at}osu.edu.

Rationale: Caspase-1 processes 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 while 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 to wildtype mice for survival after intraperitoneal challenge with live E. coli. Measurements and Main Results: Caspase-1 knockout animals were protected from bacterial challenge whereas wildtype, IL-1{beta} knockout and IL-1{beta}/IL-18 double knockout animals were not. Wildtype animals and both IL-1{beta} 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, wildtype 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: mouse knockout, septic shock, survival




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