Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice

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Abstract
Interleukin-6 null (IL-6−/−) mice have impaired liver regeneration and increased liver necrosis following partial hepatectomy that is corrected with IL-6 treatment. Following acute carbon tetrachloride (CCl4) treatment, we found that IL-6−/− mice developed increased hepatocellular injury and defective regeneration with significant blunting of signal transducer-and-activator of transcription protein 3 (STAT3) and nuclear factor-κB (NF-κB) activation and reduced hepatocyte DNA synthetic and mitotic responses. After CCl4 treatment, unlike partial hepatectomy, increased hepatocyte apoptosis was noted in IL-6−/− livers. Pretreatment with IL-6 before CCl4 reduced acute CCl4 injury and apoptosis and accelerated regeneration in both IL-6+/+ and −/− livers. Repetitive doses of CCl4 in the presence or absence of phenobarbital resulted in increased injury and fibrosis in IL-6 −/− compared with +/+ livers. After acute and chronic injury, IL-6−/− livers showed the protracted presence of α-smooth muscle actin associated with activated stellate cells, indicating a disturbed response in wound healing that progressed to fibrosis. These data provide evidence for an important role for IL-6 in reducing CCl4-induced acute and chronic liver injury and fibrosis.