SERUM LEVELS AND IN SITU EXPRESSION OF TNF-α AND TNF-α BINDING PROTEINS IN INFLAMMATORY LIVER DISEASES

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Cells respond to tumour necrosis factor-α (TNF-α) via binding to 75-kDa (type A) and 55-kDa (type B) receptors which have different intracellular signalling pathways and can also circulate as soluble molecules. Both receptors are co-expressed in many tissues, but their relative contributions to cellular TNF responses is for most situations unknown. In patients with viral and non-viral inflammatory liver diseases serum TNF-α was determined by an immunoenzymetic assay and soluble type A and B TNF receptors (TNF-αr) by enzyme linked immunological and biological assays (ELIBA). In addition, cellular expression of TNF and its binding proteins were studied in liver biopsies by an indirect immunoperoxidase technique. Secretion of TNF-α and upregulation of TNF-αr-A were particularly prominent in viral hepatitis. Strong TNF-α-in-situ production by mononuclear cells could be demonstrated in liver biopsies from patients with acute viral hepatitis. However, TNF-αr-A was detected only on hepatocytes. Serum TNF-αr-A was elevated two-fold in relative abundance over TNF-αr-B and was correlated to serum TNF-α ( r= 0.6464, P< 0.0001). Soluble TNF-αr levels normalized, when the viral hepatitis was cleared, and successful therapy of hepatitis B was associated with a temporary rise of TNF-αr-A during the initial flare of aminotransferases. Patients with alcoholic hepatitis had also evidence of TNF-α activation but clearly differed from patients with viral induced liver diseases: Soluble TNF-αr-A and TNF-αr-B were highly elevated in equal proportions. In situ analysis in liver biopsies revealed a distinctive pattern of TNF-αr expression with strong cytoplasmic staining for both TNF-αr-A and B on scattered hepatocytes in addition to infiltrating mononuclear cells. The data propose that TNF release during antiviral immune responses is predominantly associated with TNF-αr-A upregulation and shedding, whereas upregulation and shedding of TNF-αr-B is more prominent in alcoholic hepatitis. As cytotoxicity and apoptosis by TNF are mediated mainly via TNF-αr-B, our results are consistent with more severe TNF-α induced liver damage in alcoholic hepatitis as compared to viral hepatitis.