title: Caspase-7 deficiency protects from endotoxin-induced lymphocyte apoptosis and improves survival.
abstract: 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.
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA. Lamkanfi.Mohamed@gene.com
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.forename: Lilian O
authors.initials: LO
authors.lastname: Moreira
authors.forename: Patrudu
authors.initials: P
authors.lastname: Makena
authors.forename: Diana C J
authors.initials: DC
authors.lastname: Spierings
authors.forename: Kelli
authors.initials: K
authors.lastname: Boyd
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: 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
chemical_list: 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