Concanavalin A-induced hepatitis in mice is prevented by interleukin (IL)-10 and exacerbated by endogenous IL-10 deficiency.
One single intra-venous (i.v.) injection of Concanavalin A (Con A) into mice provokes a cell-mediated immunoinflammatory hepatitis. We have presently evaluated the immunopharmacological effects of exogenous interleukin (IL)-10 and the role of endogenous IL-10 in this model by using exogenous IL-10, anti-IL-10 monoclonal antibody (mAb) and mice with disrupted IL-10 gene (IL-10 KO mice). Whilst exogenous IL-10 administered in a prophylactic (1 h prior to Con A) and even "early" therapeutic fashion (30 min after Con A) reduced the elevation of transaminase activities in plasma in a dose-dependent manner, observed in control mice, these biochemical markers of liver injury were significantly increased both in IL-10 KO mice as well as in those receiving anti-IL-10 mAb. Interestingly, doses of Con A lower than 20 mg/kg that were only capable of inducing slight serological signs of hepatitis in mice, exerted marked hepatitic effects when administered to either anti-IL-10 mAb-treated mice or to IL-10 KO mice. The disease modulating effects of exogenous IL-10 and either genetical or pharmacologically-induced IL-10 deficiency were associated with profound and opposite modifications of the Con A-induced increase in the circulating levels of IFN-gamma and TNF-alpha. Relative to control animals, the blood levels of these cytokines were diminished in IL-10-treated mice and augmented in both IL-10 KO mice and anti-IL-10 mAb-treated mice. These results prove the physiological antiinflammatory role of endogenous IL-10 in Con A induced hepatitis and the beneficial effects of IL-10 treatment to prevent this condition.
Di Marco
R
R
Department of Microbiological and Gynaecological Science, Catania, Italy.
Xiang
M
M
Zaccone
P
P
Leonardi
C
C
Franco
S
S
Meroni
P
P
Nicoletti
F
F
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000517:prevention & control*; D003208:Concanavalin A / Q000633:toxicity*; D007371:Interferon-gamma / Q000097:blood / Q000187:drug effects; D016753:Interleukin-10 / Q000172:deficiency* / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000187:drug effects
D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D016753:Interleukin-10; D007371:Interferon-gamma; D000410:Alanine Transaminase