Caspase-1 regulates Escherichia coli sepsis and splenic B cell apoptosis independently of interleukin-1beta and interleukin-18.
BACKGROUND
Caspase-1 processes interleukin 1beta (IL-1beta) 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-1beta knockout mice are not protected.


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


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


RESULTS
Caspase-1 knockout animals were protected from bacterial challenge, whereas wild-type, IL-1beta knockout, and IL-1beta/IL-18 double knockout animals were not. Wild-type animals and both IL-1beta knockout and IL-1beta/IL-18 double knockout mice demonstrated significant splenic B lymphocyte apoptosis, which was absent in the caspase-1 knockout mice. Importantly, IL-1beta/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.


CONCLUSIONS
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.
Sarkar
Anasuya
A
Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Hall
Mark W
MW
Exline
Matthew
M
Hart
Judy
J
Knatz
Nina
N
Gatson
Na Tosha
NT
Wewers
Mark D
MD
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology*; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000401:mortality / Q000503:physiopathology*; D020382:Interleukin-18 / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology*; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D018805:Sepsis / Q000382:microbiology / Q000401:mortality / Q000503:physiopathology*; D013154:Spleen / Q000166:cytology*
D020382:Interleukin-18; D053583:Interleukin-1beta; D020170:Caspase 1