Hepatitis C Virus Core Protein Potentiates TNF-α-Induced NF-κB Activation through TRAF2-IKKβ-Dependent Pathway

Chung, Young Mee; Park, Kyu Jin; Choi, Sang Sam; Hwang, Soon B.; Lee, Soo Young

doi:10.1006/bbrc.2001.4936

Cited by 46 publications

(26 citation statements)

References 29 publications

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“…Because dialysis patients have an exceptionally high short-term mortality, it is less likely that the HCV-associated death risk is due to such long-term HCV complications as liver disease. Inflammation associated with chronic infections (17)(18)(19) may contribute to the increased death risk in these individuals (20,32). The currently conservative approach to HCV-infected dialysis patients (not treating them unless they have active liver pathology) may need to be revisited in light of findings that link HCV infection to short-term death.…”

Section: Perspectivementioning

confidence: 99%

“…To date, associations between traditional cardiovascular risk factors and death have not been observed in MHD patients (14,15), but a strong association between elements of the malnutrition-inflammation complex (or cachexia) syndrome (MICS) and poor clinical outcome has been observed (16). Because HCV infection is associated with increases in inflammatory markers and alterations in nutritional status in both the general population (17)(18)(19) and dialysis patients (20) and is related to poor survival in MHD patients, examining associations between HCV infection and death risk after adjustment for markers of MICS may better reveal the mechanisms that lead to mortality that is associated with HCV infection. Moreover, a larger study population allows more detailed examination of diverse subgroups and potential interactions.…”

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confidence: 99%

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Hepatitis C Virus and Death Risk in Hemodialysis Patients

Kalantar-Zadeh

Kilpatrick

McAllister

et al. 2007

Journal of the American Society of Nephrology

168

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In maintenance hemodialysis (MHD) patients, hepatitis C virus (HCV) infection is common and may be associated with poor clinical outcomes. It was hypothesized that HCV infection would be associated with high all-cause and cardiovascular mortality in these patients after controlling for demographic and clinical characteristics, including surrogates of malnutritioninflammation complex syndrome. A national database of 13,664 MHD patients who underwent HCV antibody serology testing at least once during a 3-yr interval (July 2001 through June 2004) was analyzed. Measurements included third-generation HCV enzyme immunoassay and routine laboratory measurements. The HCV enzyme immunoassay was reported positive in 1590 (12%) patients. In logistic regression models that included case mix and available surrogates of malnutrition-inflammation complex syndrome, HCV infection was associated with younger age, male gender, black race, Hispanic ethnicity, Medicaid insurance, longer dialysis vintage (duration), unmarried status, HIV infection, and smoking history. In proportional-hazards regressions, the mortality hazard ratio that was associated with HCV infection was 1.25 (95% confidence interval 1.12 to 1.39; P < 0.001). Mortality hazards were higher among incident (dialysis duration <6 mo) than prevalent HD patients. Subgroup analyses indicated that HCV was associated with higher all-cause and cardiovascular mortality across almost all clinical, demographic, and laboratory groups of patients. Hence, in MHD patients, HCV infection exhibits distinct demographic, clinical, and laboratory patterns, including associations with higher dialysis treatment vintage, and is associated with higher mortality. More diligent efforts to prevent and treat HCV infection may improve outcomes in MHD patients.

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Section: Perspectivementioning

confidence: 99%

mentioning

confidence: 99%

Hepatitis C Virus and Death Risk in Hemodialysis Patients

Kalantar-Zadeh

Kilpatrick

McAllister

et al. 2007

Journal of the American Society of Nephrology

168

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“…12,13 On the other hand, HCV infection is common in HD patients, 14,15 and is associated with a higher all-cause and cardiovascular mortality, 16,17 although it is not clear whether HCV infection per se reduces aortic compliance or not.…”

Section: Introductionmentioning

confidence: 99%

What factors accelerate aortic stiffening in hemodialysis patients? An observational study

Matsumae¹,

Abe

Nishimura³

et al. 2010

Hypertens Res

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Increased aortic stiffness is an independent predictor of death from cardiovascular disease in patients with end-stage renal disease (ESRD). Various factors that contribute to carotid-femoral pulse wave velocity (cfPWV) as a surrogate of aortic stiffness have been identified, but determinants of long-term worsening of aortic stiffness remain to be elucidated. To clarify the factors that accelerate aortic stiffness in hemodialysis patients, 148 patients with ESRD on hemodialysis were evaluated. At baseline, cfPWV and ankle-brachial blood pressure index (ABPI) were measured and clinical status including biochemical parameters, with or without hepatitis c virus (HCV) infection, diabetes mellitus (DM), cardiovascular disease, cerebrovascular disease and peripheral arterial disease at baseline, were evaluated. The cfPWV was measured again after a 3-year follow up and the annual change in cfPWV was calculated. The cfPWV decreased in 54 patients, worsened slowly in 47 (annual change in cfPWV ranged from 0 to 0.33 m s À1 per year), and worsened rapidly in 47 patients (annual change in cfPWV was more than 0.33 m s À1 per year). The prevalences of DM, HCV infection and peripheral arterial disease were the highest in the rapid progression group. Univariate analysis showed that age, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C ratio, HCV infection, ABPI and number of vasculopathies were significantly associated with annual change in cfPWV. Stepwise regression analysis identified ABPI, LDL-C/HDL-C ratio and HCV infection as independent determinants of worsening of cfPWV. Further studies are needed to investigate the mechanism of HCV-related enhancement of aortic stiffness in ESRD patients.

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“…The IB-like protein encoded by the African swine fever virus inhibits TNF-induced NF-B activation through the prevention of binding between p50 and p65 (48). It has previously been reported that HCV core protein either enhanced TNF-␣-induced NF-B activation in HEK293 and HeLa cells (12,20) or suppressed TNF-␣-induced NF-B activity in stable cells expressing HCV core (53,64). These conflicting results may be due to the difference in the cell types stably or transiently expressing core protein.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Nonstructural 5B Protein Regulates Tumor Necrosis Factor Alpha Signaling through Effects on Cellular IκB Kinase

Choi

Park

Ahn

et al. 2006

Molecular and Cellular Biology

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Hepatitis C virus (HCV) NS5B protein is a membrane-associated phosphoprotein that possesses an RNAdependent RNA polymerase activity. We recently reported that NS5A protein interacts with TRAF2 and modulates tumor necrosis factor alpha (TNF-␣)-induced NF-B and Jun N-terminal protein kinase (JNK). Since NS5A and NS5B are the essential components of the HCV replication complex, we examined whether NS5B could modulate TNF-␣-induced NF-B and JNK activation. In this study, we have demonstrated that TNF-␣-induced NF-B activation is inhibited by NS5B protein in HEK293 and hepatic cells. Furthermore, NS5B protein inhibited both TRAF2-and IKK-induced NF-B activation. Using coimmunoprecipitation assays, we show that NS5B interacts with IKK␣. Most importantly, NS5B protein in HCV subgenomic replicon cells interacted with endogenous IKK␣, and then TNF-␣-mediated IKK␣ kinase activation was significantly decreased by NS5B. Using in vitro kinase assay, we have further found that NS5B protein synergistically activated TNF-␣-mediated JNK activity in HEK293 and hepatic cells. These data suggest that NS5B protein modulates TNF-␣ signaling pathways and may contribute to HCV pathogenesis.Hepatitis C virus (HCV) is the major cause of non-A, non-B hepatitis, which often leads to liver cirrhosis and hepatocellular carcinoma (1, 14). More than 170 million individuals worldwide are infected with HCV. HCV belongs to a member of the Flaviviridae family and contains a single-stranded, positivesense RNA genome of ϳ9,600 nucleotides in length. The HCV genome encodes a single polyprotein precursor of approximately 3,010 amino acids that is cleaved by both cellular signal peptidase and viral protease to generate structural and nonstructural proteins (19,21,33,35). The N-terminally localized core and envelope proteins (E1 and E2) are viral structural proteins, and the remainders of the genome are nonstructural proteins. The nonstructural protein 5B (NS5B) is an RNAdependent RNA polymerase. The NS5B is the key enzyme that catalyzes the replication of HCV. We have previously demonstrated that NS5B is a phosphoprotein that is predominantly localized in the perinuclear region in the cytoplasm (24). Although RNA-dependent RNA polymerase activities have been demonstrated using both bacterially and baculovirus-expressed NS5B proteins (8,16,34,39,40,60), the detailed mechanism of HCV replication is poorly understood by the lack of an efficient cell culture system. The NS5B has been extensively characterized at the biochemical (8, 34) and structural levels (10, 30) and has been a prime target for inhibitors of HCV replication.The nuclear transcription factor NF-B plays a critical role in regulating the expression of many cytokines and immunoregulatory proteins (4-6). The NF-B complex is composed of homodimers or heterodimers of Rel and NF-B proteins, including NF-B1, NF-B2, p65, Rel B, and c-Rel (4). The activity of NF-B can be elevated by various stimuli, including tumor necrosis factor (TNF), interleukin 1 (IL-1), and phorbol esters (55). In most cells,...

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Hepatitis C Virus Core Protein Potentiates TNF-α-Induced NF-κB Activation through TRAF2-IKKβ-Dependent Pathway

Cited by 46 publications

References 29 publications

Hepatitis C Virus and Death Risk in Hemodialysis Patients

Hepatitis C Virus and Death Risk in Hemodialysis Patients

What factors accelerate aortic stiffening in hemodialysis patients? An observational study

Hepatitis C Virus Nonstructural 5B Protein Regulates Tumor Necrosis Factor Alpha Signaling through Effects on Cellular IκB Kinase

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