CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis.
Activated cytotoxic T-cell-mediated hepatocyte apoptosis via Fas/Fas-ligand and perforin/granzyme pathways are believed to involve the model of concanavalin A (ConA)-induced hepatitis. The purpose of the present study is to investigate whether the cytokine response modifier A (crmA) gene effectively inhibits the hepatocyte apoptosis of ConA-induced hepatitis. We examined survival rates, liver pathology, immune histological changes, and cytokine profiles from mice receiving the recombinant adenovirus vectors containing cre and/or crmA genes, transferred to the liver 3 days before ConA injection, and a crmA gene nonexpression control group. Injection of ConA into mice rapidly led to massive hepatocyte apoptosis, and infiltration of leukocytes, especially CD11b(+) inflammatory cells. In contrast, liver damage was dramatically reduced in the mice that expressed the crmA gene. However, infiltration by CD4(+) cells was not affected. The survival of the mice increased significantly to 100% in the treated group versus the control group. Furthermore, we demonstrated that interleukin (IL)-18 plays an important role in ConA-induced hepatitis, and that crmA expression significantly inhibited IL-18 secretion. Our results showed that the crmA gene effectively inhibits apoptosis induced by ConA hepatitis. This indicates a potential therapeutic usage of crmA for protection from cellular damage due to hepatitis.
Fujino
M
M
Department of Innovative Surgery, National Research Institute for Child Health and Development, Tokyo, Japan.
Kawasaki
M
M
Funeshima
N
N
Kitazawa
Y
Y
Kosuga
M
M
Okabe
K
K
Hashimoto
M
M
Yaginuma
H
H
Mikoshiba
K
K
Okuyama
T
T
Suzuki
S
S
Li
X-K
XK
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D003208:Concanavalin A; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006505:Hepatitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D022781:Hepatocytes / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology; D020382:Interleukin-18 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015843:Serpins / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014764:Viral Proteins
D020382:Interleukin-18; D015843:Serpins; D014764:Viral Proteins; D003208:Concanavalin A; D007371:Interferon-gamma; C074641:interleukin-1beta-converting enzyme inhibitor