Expression of Toll‐like receptors in chronic hepatitis C virus infection

Sato, Ken; Ishikawa, Tetsuya; Okumura, Akihiko; Yamauchi, Taeko; Sato, Sayaka; Ayada, Minoru; Matsumoto, Eiji; Hotta, Nigishi; Oohashi, Tomohiko; Fukuzawa, Yoshitaka; Kakumu, Shinichi

doi:10.1111/j.1440-1746.2006.04783.x

Cited by 65 publications

(67 citation statements)

References 27 publications

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“…It is noteworthy that hepatitis C virus (HCV) can induce anomalies in p53 function (3) and that TLR3 expression is downregulated in chronic HCV infection through an unknown mechanism (4,33). Although HCV is a singlestranded virus, which is susceptible to detection by TLR7/8, its genome also encodes regions of extensive secondary dsRNA structure that could be engaged by dsRNA-sensing receptor such as TLR3 (12).…”

Section: Discussionmentioning

confidence: 99%

p53 Regulates Toll-Like Receptor 3 Expression and Function in Human Epithelial Cell Lines

Taura

Eguma

Suico

et al. 2008

Molecular and Cellular Biology

113

117

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Section: Discussionmentioning

confidence: 99%

p53 Regulates Toll-Like Receptor 3 Expression and Function in Human Epithelial Cell Lines

Taura

Eguma

Suico

et al. 2008

Molecular and Cellular Biology

113

117

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“…While studies ex vivo of chronically infected patients show elevated levels of cytokines in the serum (4) and elevations in immune markers (Toll-like receptors [TLRs] and cytokines) in monocytes and dendritic cells (DCs) (5)(6)(7), these increased levels correlate with liver disease, which is believed to be driven by the ongoing inflammatory response, and do not correlate with reduced viral loads (8). HCV persists in part through multiple viral mechanisms employed to evade immunologic control and facilitate infection, including HCV nonstructural protease proteins NS3/4A cleavage of immune signaling adapters (9)(10)(11).…”

mentioning

confidence: 99%

Impaired Toll-Like Receptor 3-Mediated Immune Responses from Macrophages of Patients Chronically Infected with Hepatitis C Virus

Qian

Bolen

Jing

et al. 2013

Clin Vaccine Immunol

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Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the UnitedStates, with the majority of patients becoming chronically infected and a subset (20%) progressing to cirrhosis and hepatocellular carcinoma. Individual variations in immune responses may help define successful resistance to infection with HCV. We have compared the immune response in primary macrophages from patients who have spontaneously cleared HCV (viral load negative [VL؊], n ‫؍‬ 37) to that of primary macrophages from HCV genotype 1 chronically infected (VL؉) subjects (n ‫؍‬ 32) and found that macrophages from VL؊ subjects have an elevated baseline expression of Toll-like receptor 3 (TLR3). Macrophages from HCV patients were stimulated ex vivo through the TLR3 pathway and assessed using gene expression arrays and pathway analysis. We found elevated TLR3 response genes and pathway activity from VL؊ subjects. Furthermore, macrophages from VL؊ subjects showed higher produc- Approximately 3.9 million individuals in the United States, or 1.8% of the general population, are infected with HCV, and 170 million people worldwide are estimated to be infected with HCV (1). Chronic HCV infection occurs in 50 to 80% of cases, with a subset (20%) progressing to cirrhosis (2). Patients with cirrhosis are at high risk of developing hepatocellular carcinoma, which is a fatal complication of chronic HCV infection. The current combination antiviral therapy (protease inhibitor, pegylated interferon, and ribavirin) for HCV genotype 1 infection is associated with significant toxicity and results in overall viral clearance in only 66 to 75% of patients depending on other important determinants of HCV viral clearance (e.g., HIV coinfection, interleukin 28B [IL28B] status, viral load, and stage of fibrosis). Recently, inhibitors of HCV proteases have become available as a new treatment regimen and show great promise in reducing viral load in treatment-naïve genotype 1 HCV-infected patients (3).The high prevalence of chronic HCV infection indicates that for most patients, neither the innate nor the adaptive immune system is successful at eliminating the virus. While studies ex vivo of chronically infected patients show elevated levels of cytokines in the serum (4) and elevations in immune markers (Toll-like receptors [TLRs] and cytokines) in monocytes and dendritic cells (DCs) (5-7), these increased levels correlate with liver disease, which is believed to be driven by the ongoing inflammatory response, and do not correlate with reduced viral loads (8). HCV persists in part through multiple viral mechanisms employed to evade immunologic control and facilitate infection, including HCV nonstructural protease proteins NS3/4A cleavage of immune signaling adapters (9-11). Some control of HCV infection is associated with an increase in T cell responses (both CD4 ϩ and CD8 ϩ T cells), although the persistence of viremia-despite the presence of HCV-specific CD8 ϩ T cells in the liver of chronically infected patients for years-suggests they are not effecti...

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“…There are many types of TLR2 ligands, including lipoproteins, and HKLM is known as a TLR2 ligand. 23 HKLM is Gram-positive coccobacillus heat-attenuated L. monocytogenes, which usually grows in clusters in a normal medium, and has a similar morphology to that of Streptococcus. While HKLM usually causes disease in livestock, it infects humans as well, inducing intestinal diseases.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Inhibits Inflammation Induced by Heat-Killed Listeria monocytogenes

Park

Kim

Chin

et al. 2012

Journal of Medicinal Food

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Resveratrol is a polyphenolic compound in red wine that has antioxidant and cardioprotective effects in animal models. Listeria monocytogenes is a pathogen that mainly affects immunocompromised individuals and is initially detected at the cell surface or in phagosomes by toll-like receptor 2. Many antioxidants also exert anti-inflammatory activities; therefore, we evaluated the anti-inflammatory properties of resveratrol by studying the various inflammatory responses induced by heatkilled L. monocytogenes (HKLM). Resveratrol strongly blocked HKLM-induced NADPH oxidase-1 mRNA and reactive oxygen species production by macrophages. Resveratrol also suppressed monocyte chemotactic protein-1 expression, cyclooxygenase-2 expression, prostaglandin production, inducible nitric oxide (NO) synthase expression, and NO production induced by HKLM. We investigated the signaling pathway involved in the resveratrol effect. HKLM stimulated glycogen synthase kinase 3b (GSK3b) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. The involvement of GSK3b and ERK1/2 was tested using inhibitors. While the GSK3b inhibitor LiCl potentiated the effect of HKLM, the MEK inhibitor U0126 blocked these responses. Additionally, pretreatment with resveratrol blocked phosphorylation of both kinases induced by HKLM. These results suggest that HKLM is strong inducer of inflammatory mediators, and that the inhibitory effect of resveratrol may be mediated by the GSK3b and ERK1/2 pathways.KEY WORDS: COX-2 HKLM iNOS MCP-1 NADPH oxidase 1 resveratrol

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Expression of Toll‐like receptors in chronic hepatitis C virus infection

Cited by 65 publications

References 27 publications

p53 Regulates Toll-Like Receptor 3 Expression and Function in Human Epithelial Cell Lines

p53 Regulates Toll-Like Receptor 3 Expression and Function in Human Epithelial Cell Lines

Impaired Toll-Like Receptor 3-Mediated Immune Responses from Macrophages of Patients Chronically Infected with Hepatitis C Virus

Resveratrol Inhibits Inflammation Induced by Heat-Killed Listeria monocytogenes

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