T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6.
This study investigates the molecular mechanisms underlying the induction of and protection from T cell activation-associated hepatic injury. When BALB/c mice were given a single intravenous injection of concanavalin A (Con A) (> or = 0.3 mg/mouse), they developed acute hepatic injury as assessed by a striking increase in plasma transaminase levels within 24 h. Histopathologically, only the liver was injured while moderate infiltration of T cells and polymorphonuclear cells occurred in the portal areas and around the central veins. The induction of hepatic injury was dependent on the existence as well as the activation of T cells, as untreated BALB/c nu/nu mice or BALB/c mice pretreated with a T cell-specific immunosuppressive drug, FK506, failed to develop disease. Significant increases in the levels of various cytokines in the plasma were detected before an increase in plasma transaminase levels. Within 1 h after Con A injection, tumor necrosis factor (TNF) levels peaked, this being followed by production of two other inflammatory cytokines, interleukin 6 (IL-6) and IL-1. Passive immunization with anti-TNF but not with anti-IL-1 or anti-IL-6 antibody, conferred significant levels of protection. Moreover, administration of rIL-6 before Con A injection resulted in an IL-6 dose-dependent protection. A single administration of a given dose of rIL-6 completely inhibited the release of transaminases, whereas the same regimen induced only 40-50% inhibition of TNF production. More than 80% inhibition of TNF production required four consecutive rIL-6 injections. These results indicate that: (a) TNFs are critical cytokines for inducing T cell activation-associated (Con A-induced) hepatitis; (b) the induction of hepatitis is almost completely controlled by rIL-6; and (c) rIL-6 exerts its protective effect through multiple mechanisms including the reduction of TNF production.
Mizuhara
H
H
New Drug Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.
O'Neill
E
E
Seki
N
N
Ogawa
T
T
Kusunoki
C
C
Otsuka
K
K
Satoh
S
S
Niwa
M
M
Senoh
H
H
Fujiwara
H
H
D000818:Animals; D000906:Antibodies / Q000276:immunology; D003208:Concanavalin A; D005260:Female; D006520:Hepatitis, Animal / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000276:immunology*; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000906:Antibodies; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A