Genes for Interleukin-1, Interleukin-6, and Tumor Necrosis Factor are Expressed at Markedly Reduced Levels in the Livers of Patients with Severe Liver Disease

Abstract

The genes for interferon (IFN) alpha, IFN gamma, IL-1 beta, IL-6, and TNF alpha were transcribed at readily detectable levels both in liver biopsies from individuals with normal liver function and in samples of normal viable liver taken for transplantation. These results provided evidence for the concept that such multifunctional cytokines play a role in homeostasis in normal human tissues. In normal human liver, in situ hybridization studies showed that, in the absence of a detectable inflammatory response, both hepatocytes and mononuclear cells exhibited a similar degree of expression of IL-6 mRNA in keeping with the finding that IL-6 is produced by cells of different lineages. The levels of IL-1, IL-6, and TNF mRNA were found to be markedly reduced in extracts of the livers of patients with primary biliary cirrhosis and other forms of autoimmune liver disease at a time when extensive liver lesions were apparent, compared to the levels of expression of these cytokines in the livers of normal individuals. The reduced expression of IL-1, IL-6, and TNF mRNAs appeared to be a specific effect and not due to a general reduction in RNA synthesis as the IFN alpha, IFN gamma and actin mRNAs were expressed at similar levels in both normal and diseased livers. The levels of IL-1 beta, IL-6, and TNF mRNAs were also reduced in samples of liver from a patient with a drug induced fulminant hepatitis suggesting that this specific pattern of altered cytokine gene expression was characteristic of the advanced stage of severe liver disease.