Inhibition of Fas-mediated fulminant hepatitis in CrmA gene-transfected mice.
Hyperimmune response via Fas/Fas-ligand and perforin/granzyme pathways may be essential in pathogenesis of virus-induced fulminant hepatitis. CrmA inhibits activation of caspases and granzyme B, suggesting it may block these pathways. We investigated whether CrmA expression would inhibit Fas-associated lethal hepatitis in mice. We successfully generated AxCALNLCrmA, a recombinant adenovirus expressing CrmA gene with a Cre-mediated switching cassette. We increased CrmA expression level in the liver transfected with AxCALNLCrmA (10(9) pfu) by increasing administration dose (10(7)-10(9) pfu) of AxCANCre, a recombinant, adenovirus-expressing Cre gene. Injection of anti-Fas antibody into the control mice rapidly led to animal death due to massive liver apoptosis, while the apoptosis was dramatically reduced in the CrmA-expressed mice. The animal survival increased with an increase of CrmA expression. The formation of active caspase-3 was markedly inhibited in the crmA-transfected hepatocytes in vitro. These results suggest that crmA is an effective gene that can inhibit immune-related liver apoptosis.
Li
X K
XK
Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, Tokyo, Japan.
Fujino
M
M
Guo
L
L
Okuyama
T
T
Funeshima
N
N
Hashimoto
M
M
Okabe
K
K
Yaginuma
H
H
Mikoshiba
K
K
Enosawa
S
S
Amemiya
H
H
Suzuki
S
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D006520:Hepatitis, Animal / Q000201:enzymology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014162:Transfection; D019076:Transgenes / Q000235:genetics; D014764:Viral Proteins; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D061945:Caspase Inhibitors; D016177:Macrophage-1 Antigen; D015843:Serpins; D014764:Viral Proteins; D019014:fas Receptor; C074641:interleukin-1beta-converting enzyme inhibitor; C045073:Cre recombinase; D019426:Integrases; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases