Distinct downstream pathways of caspase-11 in regulating apoptosis and cytokine maturation during septic shock response.
Caspase-11 is an essential mediator of septic shock response and caspase-11-deficient mice are resistant to LPS-induced shock. Here we report that LPS-induced caspase-11 regulates lymphocyte apoptosis by activating both caspase-3 and caspase-7. The activation of caspase-11 preceded that of caspase-1 and caspases-3/-7, and in the absence of caspase-11, the activation of caspases-3/-7 was significantly reduced. The early activation of caspases-3/-7 by caspase-11 was not affected by blocking of caspase-1 activity and IL-1beta release, implying that caspase-11 activates caspases-3/-7 independently of caspase-1 activation. Furthermore, we show that caspase-11-mediated apoptosis under septic condition is Bid-independent. Our work suggests that the human homologue of caspase-11 may be an effective therapeutic target for treatment of septic shock.
Kang
S J
SJ
Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.
Wang
S
S
Kuida
K
K
Yuan
J
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053471:Caspases, Initiator; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012772:Shock, Septic / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D013154:Spleen / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002352:Carrier Proteins; D016207:Cytokines; D008070:Lipopolysaccharides; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C101136:Casp4 protein, mouse; D053148:Caspase 3; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1