scholarly journals Hepatitis C Virus Core Protein Suppresses NF-κB Activation and Cyclooxygenase-2 Expression by Direct Interaction with IκB Kinase β

2005 ◽  
Vol 79 (12) ◽  
pp. 7648-7657 ◽  
Author(s):  
Myungsoo Joo ◽  
Young S. Hahn ◽  
Minjae Kwon ◽  
Ruxana T. Sadikot ◽  
Timothy S. Blackwell ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nuclear Translocation ◽  
Core Protein ◽  
Ectopic Expression ◽  
Cyclooxygenase 2 ◽  
Necrosis Factor Alpha ◽  
Iκb Kinase ◽  
Cox 2 ◽  
The Impact

ABSTRACT In addition to hepatocytes, hepatitis C virus (HCV) infects immune cells, including macrophages. However, little is known concerning the impact of HCV infection on cellular functions of these immune effector cells. Lipopolysaccharide (LPS) activates IκB kinase (IKK) signalsome and NF-κB, which leads to the expression of cyclooxygenase-2 (COX-2), which catalyzes production of prostaglandins, potent effectors on inflammation and possibly hepatitis. Here, we examined whether expression of HCV core interferes with IKK signalsome activity and COX-2 expression in activated macrophages. In reporter assays, HCV core inhibited NF-κB activation in RAW 264.7 and MH-S murine macrophage cell lines treated with bacterial LPS. HCV core inhibited IKK signalsome and IKKβ kinase activities induced by tumor necrosis factor alpha in HeLa cells and coexpressed IKKγ in 293 cells, respectively. HCV core was coprecipitated with IΚΚβ and prevented nuclear translocation of IKKβ. NF-κB activation by either LPS or overexpression of IKKβ was sufficient to induce robust expression of COX-2, which was markedly suppressed by ectopic expression of HCV core. Together, these data indicate that HCV core suppresses IKK signalsome activity, which blunts COX-2 expression in macrophages. Additional studies are necessary to determine whether interrupted COX-2 expression by HCV core contributes to HCV pathogenesis.

scholarly journals Novel effects of the cyclooxygenase-2-selective inhibitor NS-398 on IL-1β-induced cyclooxygenase-2 and IL-8 expression in human ovarian granulosa cells

2016 ◽  
Vol 22 (6) ◽  
pp. 452-465 ◽  
Author(s):  
Hui-Ling Ou ◽  
David Sun ◽  
Yen-Chun Peng ◽  
Yuh-Lin Wu
Keyword(s):  
Inflammatory Response ◽  
Granulosa Cells ◽  
Cell Cycle Progression ◽  
Nuclear Translocation ◽  
Selective Inhibitor ◽  
Cyclooxygenase 2 ◽  
Cycle Progression ◽  
Ovarian Granulosa Cell ◽  
Cox 2 ◽  
The Impact

Ovulation is a critical inflammation-like event that is central to ovarian physiology. IL-1β is an immediate early pro-inflammatory cytokine that regulates production of several other inflammatory mediators, such as cyclooxygenase 2 (COX)-2 and IL-8. NS-398 is a selective inhibitor of COX-2 bioactivity and thus this drug is able to mitigate the COX-2-mediated production of downstream prostaglandins and the subsequent inflammatory response. Here we have investigated the action of NS-398 using a human ovarian granulosa cell line, KGN, by exploring IL-1β-regulated COX-2 and IL-8 expression. First, NS-398, instead of reducing inflammation, appeared to further enhance IL-1β-mediated COX-2 and IL-8 production. Using selective inhibitors targeting various signaling molecules, MAPK and NF-κB pathways both seemed to be involved in the impact of NS-398 on IL-1β-induced COX-2 and IL-8 expression. NS-398 also promoted IL-1β-mediated NF-κB p65 nuclear translocation but had no effect on IL-1β-activated MAPK phosphorylation. Flow cytometry analysis demonstrated that NS-398, in combination with IL-1β, significantly enhanced cell cycle progression involving IL-8. Our findings demonstrate a clear pro-inflammatory function for NS-398 in the IL-1β-mediated inflammatory response of granulosa cells, at least in part, owing to its augmenting effect on the IL-1β-induced activation of NF-κB.

scholarly journals Ectopic Expression of Hepatitis C Virus Core Protein Differentially Regulates Nuclear Transcription Factors

1998 ◽  
Vol 72 (12) ◽  
pp. 9722-9728 ◽  
Author(s):  
Anju Shrivastava ◽  
Sunil K. Manna ◽  
Ranjit Ray ◽  
Bharat B. Aggarwal
Keyword(s):  
Transcription Factors ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Inflammatory Responses ◽  
Core Protein ◽  
Ectopic Expression ◽  
Cellular Growth ◽  
Mitogen Activated Protein Kinase ◽  
The Core ◽  
Hcv Core Protein

ABSTRACT The putative core protein of hepatitis C virus (HCV) regulates cellular growth and a number of cellular promoters. To further understand its effect, we investigated the role of the core protein in the endogenous regulation of two distinct transcription factors, nuclear factor-κB (NF-κB) and activating protein-1 (AP-1), and the related mitogen-activated protein kinase kinase (MAPKK) and c-Jun N-terminal kinase (JNK). Stable cell transfectants expressing the HCV core protein suppressed tumor necrosis factor (TNF)-induced NF-κB activation. Supershift analysis revealed that NF-κB consists of p50 and p65 subunits. This correlated with inhibition of the degradation of IκBα, the inhibitory subunit of NF-κB. The effect was not specific to TNF, as suppression in core protein-expressing cells was also observed in response to a number of other inflammatory agents known to activate NF-κB. In contrast to the effect on NF-κB, the HCV core protein constitutively activated AP-1, which correlated with the activation of JNK and MAPKK, which are known to regulate AP-1. These observations indicated that the core protein targets transcription factors known to be involved in the regulation of inflammatory responses and the immune system.

scholarly journals Hepatitis C Virus Stimulates the Expression of Cyclooxygenase-2 via Oxidative Stress: Role of Prostaglandin E2 in RNA Replication

2005 ◽  
Vol 79 (15) ◽  
pp. 9725-9734 ◽  
Author(s):  
Gulam Waris ◽  
Aleem Siddiqui
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Glycogen Synthase ◽  
Rna Replication ◽  
Cyclooxygenase 2 ◽  
Prostaglandin E ◽  
Pyrrolidine Dithiocarbamate ◽  
Cox 2

ABSTRACT Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, which can lead to the development of liver cirrhosis and hepatocellular carcinoma. Recently, the activation of cyclooxygenase-2 (Cox-2) has been implicated in the HCV-associated hepatocellular carcinoma. In this study, we focus on the signaling pathway leading to Cox-2 activation induced by HCV gene expression. Here, we demonstrate that the HCV-induced reactive oxygen species and subsequent activation of NF-κB mediate the activation of Cox-2. The HCV-induced Cox-2 was sensitive to antioxidant (pyrrolidine dithiocarbamate), Ca2+ chelator (BAPTA-AM), and calpain inhibitor (N-acetyl-Leu-Leu-Met-H). The levels of prostaglandin E2 (PGE2), the product of Cox-2 activity, are increased in HCV-expressing cells. Furthermore, HCV-expressing cells treated with the inhibitors of Cox-2 (celecoxib and NS-398) showed significant reduction in PGE2 levels. We also observed the enhanced phosphorylation of Akt and its downstream substrates glycogen synthase kinase-3β and proapoptotic Bad in the HCV replicon-expressing cells. These phosphorylation events were sensitive to inhibitors of Cox-2 (celecoxib and NS-398) and phosphatidylinositol 3-kinase (LY294002). Our results also suggest a potential role of Cox-2 and PGE2 in HCV RNA replication. These studies provide insight into the mechanisms by which HCV induces intracellular events relevant to liver pathogenesis associated with viral infection.

scholarly journals Molecular Determinants for Subcellular Localization of Hepatitis C Virus Core Protein

2005 ◽  
Vol 79 (2) ◽  
pp. 1271-1281 ◽  
Author(s):  
Ryosuke Suzuki ◽  
Shinichiro Sakamoto ◽  
Takeya Tsutsumi ◽  
Akiko Rikimaru ◽  
Keiko Tanaka ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nuclear Translocation ◽  
Core Protein ◽  
Mitochondrial Outer Membrane ◽  
Cellular Trafficking ◽  
Nuclear Targeting ◽  
Diverse Range ◽  
The Core ◽  
Hcv Core Protein

ABSTRACT Hepatitis C virus (HCV) core protein is a putative nucleocapsid protein with a number of regulatory functions. In tissue culture cells, HCV core protein is mainly located at the endoplasmic reticulum as well as mitochondria and lipid droplets within the cytoplasm. However, it is also detected in the nucleus in some cells. To elucidate the mechanisms by which cellular trafficking of the protein is controlled, we performed subcellular fractionation experiments and used confocal microscopy to examine the distribution of heterologously expressed fusion proteins involving various deletions and point mutations of the HCV core combined with green fluorescent proteins. We demonstrated that a region spanning amino acids 112 to 152 can mediate association of the core protein not only with the ER but also with the mitochondrial outer membrane. This region contains an 18-amino-acid motif which is predicted to form an amphipathic α-helix structure. With regard to the nuclear targeting of the core protein, we identified a novel bipartite nuclear localization signal, which requires two out of three basic-residue clusters for efficient nuclear translocation, possibly by occupying binding sites on importin-α. Differences in the cellular trafficking of HCV core protein, achieved and maintained by multiple targeting functions as mentioned above, may in part regulate the diverse range of biological roles of the core protein.

scholarly journals Hepatitis C Virus Differentially Modulates Activation of Forkhead Transcription Factors and Insulin-Induced Metabolic Gene Expression

2010 ◽  
Vol 84 (12) ◽  
pp. 5936-5946 ◽  
Author(s):  
Arup Banerjee ◽  
Keith Meyer ◽  
Budhaditya Mazumdar ◽  
Ratna B. Ray ◽  
Ranjit Ray
Keyword(s):  
Gene Expression ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Ectopic Expression ◽  
Human Hepatocytes ◽  
Hcv Infection ◽  
Metabolic Gene ◽  
Downstream Target ◽  
The Core

ABSTRACT Chronic hepatitis C virus (HCV) infection is often associated with insulin resistance and hepatic steatosis. Insulin regulates gene expression of key enzymes in glucose and lipid metabolism by modulating the activity of specific Forkhead box transcriptional regulators (FoxO1 and FoxA2) via the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway in the liver. In this study, we observed that HCV infection of human hepatocytes impaired insulin-induced FoxO1 translocation from the nucleus to the cytoplasm and significantly reduced accumulation of FoxA2 in the nucleus. Phosphorylation of FoxO1 at Ser256, a downstream target for Akt, was inhibited in hepatocytes infected with HCV or expressing the core protein or full-length (FL) genome of HCV. Further, an interaction between FoxO1 and 14-3-3 protein, important for FoxO1 translocation, was inhibited in HCV core-expressing cells. Hepatocytes infected with HCV, expressing the core protein alone or polyprotein displayed an increased level of glucose-6-phosphatase (G6P) mRNA. On the other hand, microsomal triglycerol transfer protein (MTP) activity and apolipoprotein B (ApoB) secretion were significantly reduced in hepatocytes expressing HCV proteins. Together, these observations suggest that HCV infection or ectopic expression of the core protein either alone or together with other viral proteins from an FL gene construct differentially modulates FoxO1 and FoxA2 activation and affects insulin-induced metabolic gene regulation in human hepatocytes.

Biosynthesis and biochemical properties of the hepatitis C virus core protein.

1994 ◽  
Vol 68 (6) ◽  
pp. 3631-3641 ◽  
Author(s):  
E Santolini ◽  
G Migliaccio ◽  
N La Monica
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Biochemical Properties ◽  
Virus Core

Truncated hepatitis C virus core protein encoded in hepatocellular carcinomas

2004 ◽  
Author(s):  
Rin Yamaguchi ◽  
Seiya Momosaki ◽  
Guang Gao ◽  
Chu Hsia ◽  
Masamichi Kojiro ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Virus Core ◽  
Hepatocellular Carcinomas

Estimating the impact of hepatitis C virus therapy on future liver-related morbidity, mortality and costs related to chronic hepatitis C

2005 ◽  
Vol 42 (5) ◽  
pp. 639-645 ◽  
Author(s):  
María Buti ◽  
Ramón San Miguel ◽  
Max Brosa ◽  
Juan M. Cabasés ◽  
Montserrat Medina ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
The Impact

scholarly journals Identification of Keratin 23 as a Hepatitis C Virus-Induced Host Factor in the Human Liver

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 610 ◽  
Author(s):  
Volker Kinast ◽  
Stefan L. Leber ◽  
Richard J. P. Brown ◽  
Gabrielle Vieyres ◽  
Patrick Behrendt ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Liver Disease ◽  
Hepatitis C ◽  
Ectopic Expression ◽  
Host Factor ◽  
Hcv Infection ◽  
Mrna Levels ◽  
Structural Support ◽  
Protein Levels ◽  
Inducible Protein

Keratin proteins form intermediate filaments, which provide structural support for many tissues. Multiple keratin family members are reported to be associated with the progression of liver disease of multiple etiologies. For example, keratin 23 (KRT23) was reported as a stress-inducible protein, whose expression levels correlate with the severity of liver disease. Hepatitis C virus (HCV) is a human pathogen that causes chronic liver diseases including fibrosis, cirrhosis, and hepatocellular carcinoma. However, a link between KRT23 and hepatitis C virus (HCV) infection has not been reported previously. In this study, we investigated KRT23 mRNA levels in datasets from liver biopsies of chronic hepatitis C (CHC) patients and in primary human hepatocytes experimentally infected with HCV, in addition to hepatoma cells. Interestingly, in each of these specimens, we observed an HCV-dependent increase of mRNA levels. Importantly, the KRT23 protein levels in patient plasma decreased upon viral clearance. Ectopic expression of KRT23 enhanced HCV infection; however, CRIPSPR/Cas9-mediated knockout did not show altered replication efficiency. Taken together, our study identifies KRT23 as a novel, virus-induced host-factor for hepatitis C virus.

Sign in / Sign up

Export Citation Format

Share Document