Submitted September 9, 2008
Accepted January 12, 2009
Caspase-7 deficiency protects from endotoxin-induced lymphocyte apoptosis and improves survival
Mohamed Lamkanfi, Lilian O. Moreira, Patrudu Makena, Diana C.J. Spierings, Kelli Boyd, Peter J. Murray, Douglas R. Green, and Thirumala-Devi Kanneganti*
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, United States
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, United States
ARC Diagnostic Laboratory, St. Jude Children's Research Hospital, Memphis, TN, United States
* Corresponding author; email: thirumala-devi.kanneganti{at}stjude.org.
Extensive apoptosis of leukocytes during sepsis and endotoxic shock constitutes an important mechanism linked to the excessive mortality associated with these disorders. Caspase inhibitors confer protection from endotoxin-induced lymphocyte apoptosis and improve survival, but it is not clear which caspases mediate LPS-induced lymphocyte apoptosis and mortality. We report here that the apoptotic executioner caspase-7 was activated in splenocytes of LPS-injected mice, suggesting a role for caspase-7 in lymphocyte apoptosis. Indeed, caspase-7 deficient mice were resistant to LPS-induced lymphocyte apoptosis and were markedly protected from LPS-induced lethality independently of the excessive production of serum cytokines. These results reveal for the first time a non-redundant role for caspase-7 in vivo, and identify caspase-7 inhibition as a component of the mechanism by which caspase inhibitors protect from endotoxin-induced mortality.
