Critical involvement of interferon gamma in the pathogenesis of T-cell activation-associated hepatitis and regulatory mechanisms of interleukin-6 for the manifestations of hepatitis.
A single intravenous injection of concanavalin A (Con A) induces T-cell activation and an acute hepatitis in mice. This study investigated the role of interferon gamma (IFN-gamma) in the pathogenesis of this hepatitis model. Striking increases in the plasma levels of various cytokines, including tumor necrosis factor (TNF), interleukin-2 (IL-2), and IFN-gamma, were detected before the increase in plasma aminotransferase levels induced by Con A injection. TNF levels peaked within 2 hours, whereas IFN-gamma levels peaked at 6 hours after Con A injection. In contrast to a sharp peak of TNF levels, high IFN-gamma levels were detected for a more prolonged period. Passive immunization with anti-IFN-gamma monoclonal antibody (MAb) conferred a dose-dependent protection against liver injury in this model. This protection was observed when anti-IFN-gamma MAb was administered at least 30 minutes before Con A injection but not when given 1 hour after Con A injection. The protection from Con A-induced hepatitis was also induced by administration of rIL-6 before Con A injection. rIL-6 treatment induced significant albeit incomplete inhibition of IFN-gamma and TNF production, whereas this regimen did not affect IL-2 production. Despite striking protective effects of rIL-6 or anti-IFN-gamma MAb, comparable levels of cellular (both T cell and polymorphonuclear cell) infiltration were detected in liver sections from animals untreated, or treated with either rIL-6 or anti-IFN-gamma MAb. Moreover, electron microscopic examination showed that infiltrating T cells exhibited a blastoid appearance in all groups. These results indicate that IFN-gamma plays a critical role in the development of Con A-induced acute hepatitis and suggest that IL-6 administration can regulate the manifestation of hepatitis through mechanisms including the reduced production of inflammatory cytokines such as IFN-gamma.
Mizuhara
H
H
New Drug Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Kashima Yodogawa, Japan.
Uno
M
M
Seki
N
N
Yamashita
M
M
Yamaoka
M
M
Ogawa
T
T
Kaneda
K
K
Fujii
T
T
Senoh
H
H
Fujiwara
H
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006520:Hepatitis, Animal / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D007376:Interleukin-2 / Q000097:blood; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007376:Interleukin-2; D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007371:Interferon-gamma