Role of TNF-alpha produced by nonantigen-specific cells in a fulminant hepatitis mouse model.
In previous studies, the mechanisms of acute liver injury and virus exclusion have been examined using a model wherein HBsAg-specific CTL are injected into HBsAg transgenic (Tg) mice. The importance of the role of TNF-alpha in virus exclusion was shown, but its role in liver injury was unclear. We crossed the TNF-alpha knockout mouse and HBsAg-Tg mouse to establish the HBsAg-Tg/TNF-alpha KO mouse, and examined the influence of TNF-alpha on liver injury. The severity of liver damage, as determined by serum alanine aminotransferase activity, was approximately 100 times greater in HBsAg-Tg/TNF-alpha(+/+) than in HBsAg-Tg/TNF-alpha(-/-) mice after i.v. administration of 5 x 10(6) CTLs. This liver damage reached the peak of its severity within 24-48 h, and was restored 7 days later. Histopathological examination showed hepatocellular necrosis and inflammatory cell infiltrate 24 h after the CTL injection in HBsAg-Tg/TNF-alpha(+/+) mice but not in HBsAg-Tg/TNF-alpha(-/-) mice. The liver damage was fatal for all HBsAg-Tg/TNF-alpha(+/+) mice that received 1.5 x 10(7) CTLs. In contrast, 1.5 x 10(7) CTLs could not kill the HBsAg-Tg/TNF-alpha(-/-) mice. The TNF-alpha production level was enhanced after the CTL injection in not only intrahepatic macrophages but also other types of mononuclear cells from non-HBsAg-Tg/TNF-alpha(+/+) mice. An adoptive transfer examination revealed that severe liver damage occurred in HBsAg-Tg/TNF-alpha(-/-) mice that had received mononuclear cells from TNF-alpha(+/+) mice. In conclusion, the present study provides evidence that TNF-alpha produced by intrahepatic non-Ag-specific inflammatory cells is critical in the development of lethal necroinflammatory liver disease.
Ito
Hiroyasu
H
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu City, Japan. hito@gifu-u.ac.jp
Ando
Kazuki
K
Ishikawa
Tetsuya
T
Saito
Kuniaki
K
Takemura
Masao
M
Imawari
Michio
M
Moriwaki
Hisataka
H
Seishima
Mitsuru
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D045744:Cell Line, Tumor; D002999:Clone Cells; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology; D006524:Hepatitis, Viral, Animal / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018836:Inflammation Mediators / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D017114:Liver Failure, Acute / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000821:virology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000637:transplantation / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D000939:Epitopes; D006514:Hepatitis B Surface Antigens; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma