A pivotal role of IL-12 in Th1-dependent mouse liver injury.
Intravenous injection of Propionibacterium acnes and lipopolysaccharide (LPS) with a 7 day interval caused CD4+ T cell-dependent severe liver injury in the C57BL/6 (H-2b) mouse strain. In contrast, BALB/c (H-2d) mice were resistant to P. acnes and LPS-induced liver injury. The different susceptibilities of the two mouse strains to liver injury appeared to be closely correlated with their different abilities to produce IFN-gamma after P. acnes priming. Namely, the sensitive C57BL/6 mouse strain produced a significant level of IFN-gamma 7-10 days after P. acnes injection, whereas no significant amount of serum IFN-gamma was detected in the resistant BALB/c mouse strain. The important role of IFN-gamma in liver injury was demonstrated from the finding that in vivo administration of anti-IFN-gamma mAb abrogated P. acnes and LPS-induced liver injury in C57BL/6 mice. Moreover, it was demonstrated that in vivo administration of recombinant IL-12, a key cytokine for the induction of IFN-gamma, into mice induced P. acnes and LPS-induced liver injury in the resistant BALB/c mouse strain. Conversely, in vivo administration of anti-IL-12 mAb blocked the development of liver injury in the sensitive C57BL/6 mouse strain. Moreover, it was demonstrated that the failure of the induction of liver injury in BALB/c mice appeared to be derived from the lack of expression of IL-12 at the local site of liver in P. acnes-primed mice. These results strongly indicated that endogenous IL-12, which stimulates Th1-dominant cellular immunity and IFN-gamma production, may be an essential cytokine on the course of T cell-dependent liver injury.
Tanaka
Y
Y
Department of Immunology, Tokai University School of Medicine, Isehara, Japan.
Takahashi
A
A
Watanabe
K
K
Takayama
K
K
Yahata
T
T
Habu
S
S
Nishimura
T
T
D000818:Animals; D001483:Base Sequence; D056486:Chemical and Drug Induced Liver Injury; D004198:Disease Susceptibility; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology* / Q000502:physiology*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008099:Liver / Q000033:anatomy & histology; D008107:Liver Diseases / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011425:Propionibacterium acnes / Q000276:immunology / Q000472:pathogenicity; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D008070:Lipopolysaccharides; D018664:Interleukin-12; D007371:Interferon-gamma