Caspase-1-deficient mice have delayed neutrophil apoptosis and a prolonged inflammatory response to lipopolysaccharide-induced acute lung injury.
Caspase-1, the prototypic caspase, is known to process the cytokines IL-1beta and IL-18 to mature forms but it is unclear whether, like other caspases, it can induce apoptosis by activation of downstream protease cascades. Neutrophils are known to express caspase-1, to release IL-1beta and to undergo rapid, caspase-dependent apoptosis. We examined apoptosis and IL-1beta production in peripheral blood neutrophils of caspase-1-deficient and wild-type mice. Constitutive apoptosis of caspase-1-deficient neutrophils was delayed compared with wild-type neutrophils and LPS-mediated inhibition of apoptosis was absent, but caspase-1-deficient neutrophils were susceptible to Fas-mediated apoptosis. LPS-stimulated IL-1beta production was absent from caspase-1-deficient neutrophils. To ascertain whether these differences in apoptosis and IL-1beta production would alter the response to acute lung injury, we studied pulmonary neutrophil accumulation following intratracheal administration of LPS. Caspase-1-deficient mice showed increased, predominantly neutrophilic pulmonary inflammation, but inflammation had resolved in both wild-type and deficient animals by 72 h after LPS instillation. IL-1beta production was increased in wild-type lungs but was also detected in caspase-1-deficient mice. We conclude that caspase-1 modulates apoptosis of both peripheral blood and inflammatory neutrophils, but is not essential for IL-1beta production in the lung.
Rowe
Sarah J
SJ
Respiratory Medicine Unit, Division of Genomic Medicine, University of Sheffield, United Kingdom.
Allen
Lucy
L
Ridger
Victoria C
VC
Hellewell
Paul G
PG
Whyte
Moira K B
MK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020170:Caspase 1 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D055370:Lung Injury; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019014:fas Receptor; D020170:Caspase 1