Increased sensitivity of IL-6-deficient mice to carbon tetrachloride hepatotoxicity and protection with an IL-6 receptor-IL-6 chimera.

Abstract

Interleukin-6 (IL-6)-deficient mice were found to be much more sensitive to liver injury by carbon tetrachloride (CCl4) than mice with an intact IL-6 system. At doses of CCl4 ranging from 2 to 3.5 ml/kg body weight, mean mortality in the IL-6 gene knockout (IL-6-/-) mice was 71% at 24 hours versus 12% in normal IL-6+/+ mice. At sublethal doses, there was extensive parenchymal necrosis in the livers of IL-6-deficient mice, which was not seen in the control animals. Lipid peroxidation induced by CCl4 was up to 10-fold higher in the IL-6-/- mice. Injections of a chimeric protein containing IL-6 fused to its soluble receptor (IL-6R-IL-6 chimera) induced hepatocyte protection against CCl4 damage in both IL-6-/- and IL-6+/+ mice. Treatment with IL-6R-IL-6 restored the survival of the IL-6-/- mice to the level of IL-6+/+ animals. Free IL-6 was not effective in reducing CCl4-induced liver toxicity, but was as effective as IL-6R-IL-6 in reducing death from metastases in a murine melanoma model. Hence the IL-6R-IL-6 chimera appears to be particularly effective against chemical hepatotoxic injury.