Interleukin–10 Controls Neutrophilic Infiltration, Hepatocyte Proliferation, and Liver Fibrosis Induced by Carbon Tetrachloride in Mice

Abstract

The role of the anti–inflammatory cytokine interleukin–10 (IL–10) was investigated in the mouse model of liver injury induced by carbon tetrachloride (CCl 4). To address the role of endogenous IL–10 production, acute hepatitis was induced by CCl 4 in C57Bl/6 IL–10 gene knock out (KO) and wild–type (WT) mice. After CCl 4 challenge, serum and liver levels of tumor necrosis factor–alpha (TNF–α) and serum levels of transforming growth factor–beta 1 (TGF–β1) increased and were significantly higher in IL–10 KO mice, whereas IL–6 serum levels were only slightly increased compared with WT mice. At histological examination, the livers disclosed a significantly more prominent neutrophilic infiltration in IL–10 KO mice 12 and 24 hours after CCl 4 injection. In contrast, hepatocyte necrosis, evaluated by histological examination and serum alanine aminotransferase levels, was only marginally affected. The proliferative response of hepatocytes, assessed by the proliferating cell nuclear–antigen labeling index, was significantly increased in IL–10 KO mice, compared with WT mice 48 hours after CCl 4 injection. Finally, repeated CCl 4 injections led to more liver fibrosis in IL–10 KO mice after 7 weeks. In conclusion, endogenous IL–10 marginally affects the hepatocyte necrosis although it controls the acute inflammatory burst induced by CCl 4. During liver repair, it limits the proliferative response of hepatocytes and the development of fibrosis.