Induction of tumour necrosis factor (TNF) receptor type p55 and p75 in patients with chronic hepatitis C virus (HCV) infection

Abstract

There is evidence that TNF-alpha contributes to the pathogenesis of chronic viral hepatitis. The cellular effects of this cytokine are regulated by two specific receptors, and membranous shedding of these receptors reflects activation of the TNF system. We performed a study of TNF-alpha and functionally active soluble TNF-receptors (TNFR-p55 and -p75) in 105 patients with chronic HCV infection. In HCV RNA-positive patients a significant enhancement of TNF-alpha and both receptor types was observed compared with controls (TNF-alpha 83.8+/-91.7 pg/ml versus 18.8+/-8.4 pg/ml, P<0.001; TNFR-p55 1.4+/-0.4 ng/ml versus 0.9+/-0.2 ng/ml, P<0.0001; TNFR-p75 6.4+/-2.4 ng/ml versus 2.9+/-0.6 ng/ml, P<0.0001, respectively). The enhanced serum levels of TNF-alpha and TNFRs were reflected by a significant expression of TNFR-specific mRNA in peripheral mononuclear cells of HCV-infected patients (P<0.001). Serum aminotransferases correlated with soluble TNFR-p75 (P<0.001) but not with TNFR-p55 and TNF-alpha. We demonstrated an association of the degree of histological inflammation with both TNFRs (P<0.01). Furthermore, enhanced hepatocellular expression of TNF-alpha and TNFRs could be demonstrated by immunohistochemical staining in HCV-infected patients. Sixty-eight out of 105 patients were treated with interferon-alpha (IFN-alpha) (3x10(6)U x 3/week). Pretreatment levels of TNF-alpha and TNFRs did not differ between responders and non-responders. Our results demonstrate that TNF-alpha and TNFRs are enhanced in chronic HCV infection and reflect histological activity of the disease. This up-regulation of TNFRs might modify host response and potentially contribute to liver damage in chronic HCV infection.

Fig. 1

Serum levels of TNF-α, sTNFR-p55 and TNFR-p75 in 105 patients with chronic HCV infection and different histological activity (68 patients with histological activity index (H.A.I.) 1–4 and 37 patients with H.A.I. 5–9, respectively) compared with 48 healthy controls. Data are presented using the box plot model. Significance is given as *P < 0.001 (Mann–Whitney U-test).

Fig. 2

Correlation of sTNFR-p55 and -p75 levels with the histological activity index (H.A.I.) in HCV-infected patients. (Spearman rank regression analysis.)

Fig. 3

Correlation of sTNFR-p75 with aminotransferases AST and ALT in HCV-infected patients calculated by a Spearman rank regression analysis.

Fig. 4

Correlation of aminotransferases AST and ALT with the histological activity index (H.A.I.) in HCV-infected patients calculated by Spearman rank regression analysis.

Fig. 5

Analysis of mRNA assisted polymerase chain reaction (PCR) amplification in peripheral blood mononuclear cells (PBMC) shows a significant expression of TNFR-p55 and -p75-specific RNA in HCV RNA-positive patients compared with healthy controls. GPDH mRNA analysis is given for comparison. Co, Control; H.A.I., histological activity index.

Fig. 6

(See next page.) Hepatic expression of TNF-α (a), cellular TNFR-p55 (b) and cellular TNFR-p75 (c) in a patient with a normal liver histology.

Fig. 7

(See p. 275.) Hepatic expression of TNF-α (a), sTNFR-p55 (b) and TNFR-p75 (c) in a HCV-infected patient with a histological activity index (H.A.I.) > 6. TNFR-p55 could be demonstrated in the nucleus in a few hepatocytes, whereas TNFR-p75 showed a strong membranous expression.