Combinatorial effects of interleukin 10 and interleukin 4 determine the progression of hepatic inflammation following murine enteric parasitic infection


  • Potential conflict of interest: Nothing to report.


Mice lacking the immunoregulatory cytokine interleukin 10 (IL-10) develop necrotizing hepatitis after infection with Trichinella spiralis, and inflammation is dependent on the migration of intestinally activated CD4+ T cells into the liver. Hepatic production of IL-4 is elevated in these mice, and we hypothesized that it plays a role in the development of hepatic pathology. Wild-type (WT), IL-10 knockout (KO), IL-4 KO, and IL-10/IL-4 KO mice were orally infected, and disease progression was followed by histological examination, alanine aminotransferase assays, and flow cytometric analysis of hepatocellular content. Both IL-10 KO and IL-10/IL-4 KO mice experienced hepatocellular injury, but only IL-10 KO mice advanced to a necrotic phase. Hepatic CD4+ T cells were the major source of IL-4, and IL-10 regulated the number of intestinally-derived CD4+IL-4+ cells. Sequestration of activated neutrophils in the liver required IL-4, and neutrophil depletion prevented progression to overt necrosis. Adoptive transfer of intestinal WT CD4+ T cells inhibited neutrophil accumulation and inflammation, but their regulatory effects did not require IL-10 signaling. Conclusion: The absence of IL-10 led to hepatocyte injury during infection, but IL-4 was necessary for the development of neutrophil-dependent necrosis. These studies provide new insight into the combinatorial role of these cytokines and their targets in the generation and progression of hepatic inflammation. (HEPATOLOGY 2010;)