Bimodal role of endogenous interleukin-6 in concanavalin A-induced hepatitis in mice.
Acute concanavalin A (Con A)-induced hepatitis in mice is an animal model for hepatic injury induced by activated T cells. The evolution of hepatic involvement can be followed from hour to hour by measuring serum transaminase levels. We investigated the possible role of endogenous interleukin-6 (IL-6) in this model. We found serum IL-6 levels and splenic IL-6 mRNA during Con A-induced hepatitis to be significantly lower in interferon-gamma (IFN-gamma)-deficient mice, which are resistant against the Con A-induced syndrome, than in wild-type ones, suggesting that systemic IL-6 production favors development of hepatic injury. However, IL-6-deficient mice proved to be more susceptible to the disease than wild-type mice, indicating that endogenous IL-6 plays a predominantly hepatoprotective role. Experiments in which wild-type mice were treated with anti-IL-6 antibodies, before or after Con A challenge, allowed us to reconcile these contrasting observations. The antibody injections resulted in a biphasic alteration of serum IL-6 levels, initial neutralization being followed by rebound increased levels due to accumulation of IL-6 in the form of antigen-antibody complexes. The effect of antibody on disease severity differed depending on the time of injection. Antibody injection at 2.5 h post Con A resulted in delayed disease manifestation, whereas treatment initiated before Con A resulted in accelerated disease. We conclude that endogenous IL-6 plays a bimodal role. IL-6 present before Con A challenge as well as that induced in the very early phase after Con A injection triggers hepatoprotective pathways. Continuation of IL-6 production beyond this early phase, by some other pathway, seems to be harmful to hepatocytes.
Tagawa
Y
Y
Laboratory of Immunobiology, Rega Institute, University of Leuven, Belgium.
Matthys
P
P
Heremans
H
H
Dillen
C
C
Zaman
Z
Z
Iwakura
Y
Y
Billiau
A
A
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D003208:Concanavalin A / Q000633:toxicity*; D007371:Interferon-gamma / Q000172:deficiency*; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C
D015850:Interleukin-6; D003208:Concanavalin A; D007371:Interferon-gamma