Caspase-7 deficiency protects from endotoxin-induced lymphocyte apoptosis and improves survival.
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 lipopolysaccharide (LPS)-induced lymphocyte apoptosis and mortality. We report here that the apoptotic executioner caspase-7 was activated in the 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 nonredundant 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.
Lamkanfi
Mohamed
M
Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA. Lamkanfi.Mohamed@gene.com
Moreira
Lilian O
LO
Makena
Patrudu
P
Spierings
Diana C J
DC
Boyd
Kelli
K
Murray
Peter J
PJ
Green
Douglas R
DR
Kanneganti
Thirumala-Devi
TD
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics; D053148:Caspase 3 / Q000172:deficiency / Q000235:genetics; D053179:Caspase 7 / Q000172:deficiency* / Q000502:physiology; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D019446:Endotoxemia / Q000097:blood / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D004731:Endotoxins / Q000008:administration & dosage / Q000633:toxicity*; D004789:Enzyme Activation; D007274:Injections, Intraperitoneal; D008214:Lymphocytes / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000276:immunology / Q000473:pathology
D018925:Chemokines; D016207:Cytokines; D004731:Endotoxins; C044101:endotoxin, Escherichia coli; C505409:Casp3 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7; D020170:Caspase 1