Apoptosis-related proteins, BCL-2, BAX, FAS, FAS-L and PCNA in liver biopsies of patients with chronic hepatitis B virus infection

Abstract

While the elimination of hepatitis B virus (HBV) is a common phenomenon at the end of the acute phase of disease, the persistence of HBV is characteristic for chronic hepatitis (CHB). Recent evidence indicates that the elimination of HBV is achieved by FAS/FAS-L induced apoptosis of infected hepatocytes. The aim of this study was to test the hypothesis that HBV persistence in the hepatocytes of CHB patients is due to the delayed onset of apoptosis caused by altered FAS/FAS-L interactions between lymphocytes and hepatocytes. The expression of FAS, FAS-L, BAX, BCL-2, ICE and PCNA in the liver biopsies of 55 patients (14 HBsAg positive, 20 patients with alcoholic hepatopathy, 21 patients with other hepatopathies) was tested by immunohistochemistry. Apoptosis of hepatocytes was evaluated by morphological as well as by TUNEL method. The results were correlated with a grading/staging score and analysed statistically using a one way analysis of variance and the Duncan test. Significantly highernumbers of BAX positive hepatocytes were observed in HBsAg positive patients when compared to control groups. Similarly, both BAX and FAS positive lymphocytes were more frequent in HBsAg positive patients. FAS-L positive lymphocytes and hepatocytes were numerous in all patient groups. Increased numbers of BAX positive hepatocytes in CHB may reflect the increased readiness of these cells to undergo apoptosis. However, the increased numbers of both BAX and FAS positive lymphocytes in CHB suggest that these cells may be particularly sensitive to FAS-L mediated apoptosis potentially resulting in lowered viability of these lymphocytes. This may explain, at least in part, the defective removal of virus-infected cells in chronic hepatitis. However, we cannot rule out the possibility that survival of hepatocytes during CHB may be due to other mechanisms such as defects in apoptosis activation triggered by CD40, defects involving DNase and/or other caspases downstream in the apoptotic cascade within these cells, or to defects in CTL function.

Profile of expression of certain markers of apoptosis in chronic hepatitis C and hepatitis B patients in an Egyptian population

“…These findings are also in agreement with those reported by Ehrmannet al [45], who found that both Bax-and Fas-positive PBMCs were more frequent in HBsAg-positive patients when compared to control groups. The increased numbers of both Bax-and Fas-positive PBMCs in CHB suggest that these cells may be particularly sensitive to Fas-mediated apoptosis, potentially resulting in lowered viability of these lymphocytes, which may explain, at least in part, the defective removal of virus-infected cells in chronic hepatitis.…”

“…In addition, FasL-bearing hepatocytes in CHB may also induce apoptosis in CTLs expressing Fas. Such a mechanism may contribute to CTL escape of HBV-infected hepatocytes [45] However, these results contradict those of Toubi et al [35], who demonstrated similar Fas expression on activated T cells of HBV patients compared with controls.…”

Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair

“…[38][39][40][41] These results suggest persistent abnormal signaling in these conditions, possibly because of chronic IL-6 overproduction, may be mediating some of the cellular deficiencies observed in these chronic states. An association of IL-6 and STAT-3 activation with fatty liver disease has been demonstrated, 13 with ob/ob mice exhibiting persistent STAT3 signaling as well as profound steatosis and abnormal liver regeneration.…”

Variations in the serum concentrations of soluble Fas and soluble Fas ligand in Vietnamese patients infected with hepatitis B virus

“…The expression of both Fas and FasL can be up-regulated on hepatocytes of hepatitis patients with differing clinical status [Mochizuki et al, 1996;Strand et al, 1996;Luo et al, 1997;Iio et al, 1998;Ehrmann et al, 2000;Rivero et al, 2002]. In hepatocellular carcinoma (HCC), however, simultaneous down-regulation of Fas and up-regulation of FasL expression on hepatocytes is observed [Strand et al, 1996].…”