Suppression of Apoptotic Cell Death by Hepatitis C Virus Core Protein

Ray, Ratna B.; Meyer, Keith

doi:10.1006/viro.1996.0644

Cited by 261 publications

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“…Recent studies showed that the HCV core protein exerts both proapoptotic and antiapoptotic properties in different experimental conditions. [9][10][11][12] The HCV core protein can modulate the immune response by activation of transcription factors, such as nuclear factor-B and activator protein-1, thereby inducing the production of proinflammatory cytokines. 46 Thus, HCV proteins might modulate hepatocyte apoptosis by indirect rather than by direct mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…2 In addition to CD95L and other cytokines, both structural and nonstructural HCV proteins have been shown to modulate the sensitivity of hepatocytes for cell death. [9][10][11][12][13] Cells undergoing apoptosis show a sequence of morphologic features including membrane blebbing, cellular shrinkage, and condensation of chromatin. Recent studies showed that the key morphologic alterations of apoptosis are essentially mediated by a family of conserved intracellular proteases, called caspases.…”

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Caspase activation correlates with the degree of inflammatory liver injury in chronic hepatitis C virus infection

et al. 2001

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Hepatitis C virus (HCV) infection is a major cause of liver disease characterized by inflammation, cell damage, and fibrotic reactions of hepatocytes. Apoptosis has been implicated in the pathogenesis, although it is unclear whether proteases of the caspase family as the central executioners of apoptosis are involved and how caspase activation contributes to liver injury. In the present study, we measured the activation of effector caspases in liver biopsy specimens of patients with chronic HCV infection. The activation of caspase-3, caspase-7, and cleavage of poly(ADP-ribose)polymerase (PARP), a specific caspase substrate, were measured by immunohistochemistry and Western blot analysis by using antibodies that selectively detect the active truncated, but not the inactive precursor forms of the caspases and PARP. We found that caspase activation was considerably elevated in liver lobules of HCV patients in comparison to normal controls. Interestingly, the immunoreactive cells did yet not reveal an overt apoptotic morphology. The extent of caspase activation correlated significantly with the disease grade, i.e., necroinflammatory activity. In contrast, no correlation was observed with other surrogate markers such as serum transaminases and viral load. In biopsy specimens with low activity ( Hepatitis C virus (HCV) infection is one of the major causes of liver disease with an increased risk of cirrhosis and hepatocellular carcinoma. The infection has a high propensity to chronicity, and the majority of HCV carriers have histologic evidence for liver inflammation, cell damage, and fibrotic reactions of hepatocytes. The mechanisms responsible for HCVmediated liver cell damage are poorly understood, and both immune-mediated reactions and direct cytopathic effects of HCV may be involved in its pathogenesis. It has been suggested that apoptosis plays an important role in HCV-associated liver injury, 1-4 although it is unclear which cellular and molecular mechanisms participate in the process.One of the best-defined apoptotic pathways is mediated by the death receptor CD95, a member of the tumor necrosis factor superfamily that is constitutively expressed on hepatocytes. 5 Experiments in mice have shown that agonistic CD95 antibodies cause massive liver cell lysis, resulting in increased serum levels of transaminases and death from fulminant hepatic failure. 6 In patients with chronic HCV infection, expression of CD95 is increased and associated with disease activity and the severity of liver inflammation. 7,8 When HCV-specific T cells migrate towards hepatocytes and recognize viral antigens through the T-cell receptor, they become activated and inducibly express the ligand CD95L that can transduce the apoptotic death signal to CD95-bearing hepatocytes. 2 In addition to CD95L and other cytokines, both structural and nonstructural HCV proteins have been shown to modulate the sensitivity of hepatocytes for cell death. [9][10][11][12][13] Cells undergoing apoptosis show a sequence of morphologic features including membrane...

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Section: Discussionmentioning

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Caspase activation correlates with the degree of inflammatory liver injury in chronic hepatitis C virus infection

et al. 2001

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“…HCV core has been described as being associated with lymphotoxin-b receptor, TNF-receptor 1, apolipoprotein AII, hnRNP and a bZIP transcription factor (Barba et al, 1997;Chen et al, 1997;Hsieh et al, 1998;Sabile et al, 1999). Evidence exists that HCV core may have an e ect upon cell transformation (Jin et al, 2000) and apoptosis (Marusawa et al, 1999;Ray et al, 1996Ray et al, , 1998Ruggieri et al, 1997); however, the biological consequences of core ectopic expression depend on the levels of expression achieved, the cell type utilized and the cellular environment (Honda et al, 2000;Zhu et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Activation of the interferon-inducible protein kinase PKR by Hepatocellular carcinoma derived-Hepatitis C virus core protein

et al. 2001

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Hepatitis C virus (HCV) is a major etiological agent of chronic liver disease and hepatocellular carcinoma (HCC). We demonstrate herewith that HCV core proteins encoded by sequences isolated from HCC tumor tissues, but not those derived from their non-tumor counterparts in the same liver, co-localise in vitro and in vivo and co-immunoprecipitate with PKR in hepatocytic Huh7 cells. We show that this association in fact augments the autophosphorylation of PKR and the phosphorylation of the translation initiation factor eIF2a, which are two markers of PKR activity. The present study therefore identi®es a novel model of viruscell interactions whereby a viral protein, the HCV core, activates PKR activity. Oncogene (2001) 20, 5836 ± 5845.

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“…In different experimental conditions, the HCV core protein has been reported either to sensitize cells to death receptor-mediated apoptosis or to exert inhibitory effects through the activation of nuclear factor (NF)-B and induction of antiapoptotic gene products, including Bcl-2 and Bcl-x L . [15][16][17][18] It has not been determined whether steatosis or host factors such as BMI influence the apoptotic process in chronic hepatitis C. Interestingly, hepatocyte apoptosis recently was shown to be a prominent feature of nonalcoholic fatty liver disease. 19 In that study, a positive correlation was observed between hepatocyte apoptosis and both hepatic inflammatory activity and fibrosis, implicating a role for the apoptotic process in the progression of fatty liver disease.…”

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Steatosis and liver cell apoptosis in chronic hepatitis C: A mechanism for increased liver injury

et al. 2004

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Steatosis is increasingly recognized as a cofactor influencing the progression of fibrosis in chronic hepatitis C; however, the mechanisms by which it contributes to liver injury remain uncertain. We studied 125 patients with chronic hepatitis C to assess the effect of steatosis on liver cell apoptosis and the expression of Bcl-2, Bcl-x L , Bax, and tumor necrosis factor alpha (TNF-␣) and the relationship between liver cell apoptosis and disease severity. A significant increase in liver cell apoptosis was seen in liver sections with increasing grade of steatosis (r ‫؍‬ 0.42; P < .0001). Hepatic steatosis and previous heavy alcohol consumption were the only two variables independently associated with the apoptotic index. Increasing steatosis was associated with decreased Bcl-2 mRNA levels and an increase in the proapoptotic Bax/Bcl-2 ratio (r ‫؍‬ ؊0.32, P ‫؍‬ .007; and r ‫؍‬ 0.27, P ‫؍‬ .02, respectively). In the absence of steatosis, increased liver cell apoptosis was not associated with stellate cell activation or fibrosis (r ‫؍‬ 0.26, P ‫؍‬ .11; r ‫؍‬ 0.06, P ‫؍‬ .71, respectively). In contrast, in the presence of steatosis, increasing apoptosis was associated with activation of stellate cells and increased stage of fibrosis (r ‫؍‬ 0.35, P ‫؍‬ .047; r ‫؍‬ 0.33, P ‫؍‬ .03, respectively), supporting the premise that the steatotic liver is more vulnerable to liver injury. In patients with hepatitis C virus genotype 3, there was a significant correlation between TNF-␣ mRNA levels and active caspase-3 (r ‫؍‬ 0.54, P ‫؍‬ .007). In conclusion, these observations suggest a mechanism whereby steatosis contributes to the progression of liver injury in chronic hepatitis C. Further investigation will be required to determine the molecular pathways responsible for the proapoptotic effect of steatosis and whether this increase in apoptosis contributes directly to fibrogenesis.

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Suppression of Apoptotic Cell Death by Hepatitis C Virus Core Protein

Cited by 261 publications

References 0 publications

Caspase activation correlates with the degree of inflammatory liver injury in chronic hepatitis C virus infection

Caspase activation correlates with the degree of inflammatory liver injury in chronic hepatitis C virus infection

Activation of the interferon-inducible protein kinase PKR by Hepatocellular carcinoma derived-Hepatitis C virus core protein

Steatosis and liver cell apoptosis in chronic hepatitis C: A mechanism for increased liver injury

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