INDUCTION OF TUMOR-NECROSIS-FACTOR (TNF) RECEPTOR-TYPE P55 AND P75 INPATIENTS WITH CHRONIC HEPATITIS-C VIRUS (HCV) INFECTION

There is evidence that TNF-alpha contributes to the pathogenesis of ch ronic viral hepatitis. The cellular effects of this cytokine are regul ated by two specific receptors, and membranous shedding of these recep tors reflects activation of the TNF system. We performed a study of TN F-alpha and functionally active soluble TNF-receptors (TNFR-p55 and -p 75) in 105 patients with chronic HCV infection. In HCV RNA-positive pa tients a significant enhancement of TNF-alpha and both receptor types was observed compared with controls (TNF-alpha 83.8 +/- 91.7 pg/ml ver sus 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-sp ecific 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 associa tion 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-in fected patients. Sixty-eight out of 105 patients were treated with int erferon-alpha (IFN-alpha) (3 x 10(6)U x3/week). Pretreatment levels of TNF-alpha and TNFRs did not differ between responders and non-respond ers. 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 potential ly contribute to liver damage in chronic HCV infection.