Neutralization of tumor necrosis factor abrogates hepatic failure induced by alpha-galactosylceramide without attenuating its antitumor effect in aged mice.
OBJECTIVE
The functions of mouse liver NK1.1+ T (NKT) cells stimulated with alpha-galactosylceramide (alpha-GalCer) are enhanced age dependently, and the antitumor and anti-metastatic effect in the liver is dependent on IFN-gamma. However, hepatic injury is independent of IFN-gamma and Fas/Fas-ligand dependent. The aim of this study is to investigate how tumor necrosis factor is involved in the alpha-GalCer-mediated immune phenomena.


METHODS
C57BL/6 mice were intraperitoneally treated with anti-TNF antibody 1 h before alpha-GalCer injection, and Fas-ligand expression of NKT cells, the serum ALT levels and histopathological findings of the liver, kidney and lung and mortality after alpha-GalCer injection were evaluated. IFN-gamma production and antitumor immunity in the liver after the intravenous injection of EL-4 cells were also assessed.


RESULTS
Serum TNF levels after alpha-GalCer injection increased age dependently in mice. Anti-TNF Ab reduced Fas-ligand (Fas-L) expression of NKT cells while it completely inhibited organ injuries induced by alpha-GalCer and thereby reduced the mortality of old mice, whereas it did not affect the IFN-gamma production from NKT cells, the antitumor immunity in the liver nor the mouse survival after EL-4 injection.


CONCLUSIONS
NKT cells activated by alpha-galactosylceramide participated in either antitumor immunity or hepatic injury using IFN-gamma and TNF/Fas-L, respectively.
Inui
Takuo
T
Department of Microbiology, National Defense Medical College, Namiki, Tokorozawa, Japan.
Nakashima
Hiroyuki
H
Habu
Yoshiko
Y
Nakagawa
Ryusuke
R
Fukasawa
Masashi
M
Kinoshita
Manabu
M
Shinomiya
Nariyoshi
N
Seki
Shuhji
S
D000375:Aging; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000633:toxicity*; D007371:Interferon-gamma / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000254:growth & development / Q000473:pathology; D017093:Liver Failure / Q000139:chemically induced / Q000517:prevention & control*; D008223:Lymphoma; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000970:Antineoplastic Agents; D005699:Galactosylceramides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase