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TLR and hepatitis C

Stephanie T Chan, Jiyoung Lee, Mansi Narula, J-H James Ou
: Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an important adapter molecule that mediates the TNFR family and interleukin-1/Toll-like receptor (IL-1/TLR) signaling cascades. These pathways are important for the host to control viral infections. In this report, we demonstrated that hepatitis C virus (HCV) depleted TRAF6 from its host cells through a post-translational mechanism. This depletion was independent of proteasomes, as it was not affected by the proteasome inhibitor MG132, but it was suppressed by bafilomycin A1, which led to the association of TRAF6 with autophagosomes...
September 28, 2016: Journal of Virology
Yuehua Wang, Bin Li, Jinyan Zhu, Qi Zhang, Xiuyan Zhang, Li Li, Yan Ma, Xianjun Meng
The protective effects of Lonicera caerulea berry extract (LCBE) against hepatic inflammation and the underlying mechanisms were investigated in a rat model of lipopolysaccharide (LPS)-induced chronic liver inflammation. Male Sprague-Dawley rats were injected with LPS (200 μg per kg bw) with or without LCBE co-administration (50, 100 and 200 mg per kg bw intragastrically once daily) for 4 weeks. We found that LCBE supplementation inhibited the increase in Toll-like receptor (TLR)2 and TLR4 expression induced by LPS, while preventing glutathione depletion and reactive oxidative species generation and abrogating increases in C-reactive protein and interleukin-6 levels, restoring alanine and aspartate aminotransferase activities, and blocking the phosphorylation of p38 and c-Jun N-terminal kinase mitogen-activated protein kinases (MAPKs)...
October 12, 2016: Food & Function
Benjamin Krämer, Claudia Finnemann, Beatriz Sastre, Philipp Lutz, Andreas Glässner, Franziska Wolter, Felix Goeser, Pavlos Kokordelis, Dominik Kaczmarek, Hans-Dieter Nischalke, Christian P Strassburg, Ulrich Spengler, Jacob Nattermann
BACKGROUND: Immuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity. METHODS: A total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both...
2016: PloS One
Chuan-Mo Lee, Tsung-Hui Hu, Sheng-Nan Lu, Jing-Houng Wang, Chao-Hung Hung, Chien-Hung Chen, Yi-Hao Yen
BACKGROUND: Toll-like receptors (TLRs) are effectors of the innate immune system that are able to recognize hepatitis C virus (HCV) and give rise to an immune response. Failure of interferon (IFN)-α-based treatment is related to host immunity. Therefore, we sought to study the clinical importance of TLRs in HCV genotype 1 patients who received pegylated IFN (PEG-IFN) plus ribavirin (RBV) therapy. METHODS: We enrolled 79 treatment-naïve patients with HCV genotype 1...
2016: BMC Gastroenterology
Yuhan Chen, Zhaochong Zeng, Xiaoyun Shen, Zhifeng Wu, Yinying Dong, Jason Chia-Hsien Cheng
Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB)...
2016: International Journal of Molecular Sciences
Yue-Min Nan, Shan-Shan Su, Xue-Min Niu, Su-Xian Zhao, Yu-Guo Zhang, Rong-Qi Wang, Ling-Bo Kong, Huan He, Huan-Wei Zheng, Dian-Xing Sun
OBJECTIVE: To investigate the regulation mechanism of T cell immunoglobulin and mucin domain-3 (Tim-3) combined with toll-like receptor 3 (TLR3) or TLR4 on antiviral immune and inflammatory response in patients with chronic hepatitis C virus (HCV) infection. METHODS: Patients with chronic HCV infection and healthy control subjects were recruited. Patients received interferon (IFN)-α based therapy. Plasma galectin-9 (Gal-9) was quantitated. Peripheral blood mononuclear cells (PBMCs) were cultured with TLR3 or TLR4 agonists, alone or in combination with Tim-3 antagonist...
August 2016: Journal of International Medical Research
Swee Lin G Chen Yi Mei, Jodie Burchell, Narelle Skinner, Rosie Millen, Gail Matthews, Margaret Hellard, Gregory J Dore, Paul V Desmond, Vijaya Sundararajan, Alexander J Thompson, Kumar Visvanathan, Joe Sasadeusz
BACKGROUND: Mechanisms by which spontaneous clearance of acute hepatitis C occurs are unclear. A critical role for the innate immune system and IFNL4 polymorphisms has been proposed. This study investigates whether Toll-like receptor (TLR) expression and signaling during acute hepatitis C correlates with clinical outcomes. METHODS: Participants identified from the Australian Trial in Acute Hepatitis C and the Networks study were followed longitudinally from the time of diagnosis of acute hepatitis C...
September 1, 2016: Journal of Infectious Diseases
Man He, Min Wang, Ying Huang, Wenju Peng, Zizheng Zheng, Ningshao Xia, Jian Xu, Deying Tian
Hepatitis E virus (HEV) genotype 1 infection is common and can emerge as outbreaks in developing areas, thus posing a threat to public health. However, due to the absence of feasible animal models, the mechanism of HE pathogenesis remains obscure. The HEV pathogenic mechanism has been suggested to be mediated by the immune system and not by direct viral duplication. We firstly discovered that the open reading frame 3 (ORF3) protein of genotype 1 HEV downregulates TLR3-mediated NF-κB signaling in Human A549 Lung Epithelial Cells (A549 cells) which were exposed to different TLR agonists associated with viral nucleic acids...
2016: Scientific Reports
Besma Aouar, Denisa Kovarova, Sebastien Letard, Albert Font-Haro, Jonathan Florentin, Jan Weber, David Durantel, Laurence Chaperot, Joel Plumas, Katerina Trejbalova, Jiri Hejnar, Jacques A Nunès, Daniel Olive, Patrice Dubreuil, Ivan Hirsch, Ruzena Stranska
Crosslinking of regulatory immunoreceptors (RR), such as BDCA-2 (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses production of type-I interferon (IFN)-α/β and other cytokines in response to Toll-like receptor (TLR) 7/9 ligands. This cytokine-inhibitory pathway is mediated by spleen tyrosine kinase (Syk) associated with the ITAM-containing adapter of RR. Here we demonstrate by pharmacological targeting of Syk that in addition to the negative regulation of TLR7/9 signaling via RR, Syk also positively regulates the TLR7/9 pathway in human pDCs...
2016: PloS One
Maria J Citores, Sofia Pérez-Pulgar, Ana Duca, Gonzalo Crespo, Sara de la Fuente, Carlos Vilches, Miquel Navasa, Valentin Cuervas-Mons
Liver transplantation activates the innate immune system through toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the association of single-nucleotide polymorphisms in TLR genes with the severity of hepatitis C virus recurrence after liver transplantation (LT). This is a two-center study of 176 adult patients who received a first LT from deceased donors for hepatitis C virus (HCV) cirrhosis. Eleven polymorphisms were evaluated by real-time polymerase chain reaction and melting curves analyses: TLR1 (Asp248Ser and Ser602Ile), TLR2 (Arg753Gln), TLR3 (Leu412Phe), TLR4 (Asp299Gly), TLR5 (Arg392Stop), TLR6 (Ser249Pro), TLR7 (Gln11Leu), TLR8 (Met1Val), and TLR9 (-1237T/C and -1486C/T)...
July 2016: Clinical Transplantation
Zia-Ur-Rehman Farooqi, Samar H K Tareen, Jamil Ahmed, Najam-Us-Sahar S Zaidi
Hepatitis C virus (HCV) triggers coordinated innate and adaptive response in host cell. HCV genome and proteins of the replicating virus are recognized as non-self-antigens by host cell to activate Toll Like Receptors (TLRs). Activated TLRs ultimately express cytokines, which can clear virus either by activating interferon (IFN), protein kinase C (PKC) and RNA Lase system or through activation of cytotoxic T-lymphocytes. Interleukin-12 (IL-12) is a potent antiviral cytokine, capable of clearing HCV by bridging both innate and adaptive antiviral immune response...
2016: Protein and Peptide Letters
Xin Liu, Jing-Hui Guan, Ben-Chun Jiang, Zhen-Sheng-Nan Li, Guang-Ze Zhu
Regulatory T cells (Tregs) and interleukin-17-producing T helper (Th17) cells were mutually antagonistic in the pathogenesis of chronic hepatitis C virus (HCV) infection. However, the regulation of imbalance between Tregs and Th17 cells was poorly understood in HCV infection. A recent report revealed the immunomodulatory role of Toll-like receptor (TLR) 2 in regulating the balance of Tregs/Th17 functions in multiple sclerosis. Thus, the aim of the current study was to assess the effect of TLR2 stimulation on the suppressive function of Tregs and Th17 differentiation in chronic hepatitis C...
July 2016: Viral Immunology
J P Ren, R S Ying, Y Q Cheng, L Wang, M El Gazzar, G Y Li, S B Ning, J P Moorman, Z Q Yao
Host innate and adaptive immune responses must be tightly regulated by an intricate balance between positive and negative signals to ensure their appropriate onset and termination while fighting pathogens and avoiding autoimmunity; persistent pathogens may usurp these regulatory machineries to dampen host immune responses for their persistence in vivo. Here, we demonstrate that miR146a is up-regulated in monocytes from hepatitis C virus (HCV)-infected individuals compared to control subjects. Interestingly, miR146a expression in monocytes without HCV infection increased, whereas its level in monocytes with HCV infection decreased, following Toll-like receptor (TLR) stimulation...
October 2016: Journal of Viral Hepatitis
Jun Ren, Shanshan Meng, Bingdi Yan, Jinyan Yu, Jing Liu
Protectin D1 (PD1) is a bioactive product generated from docosahexaenoic acid, which may exert anti-inflammatory effects in various inflammatory diseases. However, the underlying molecular mechanism of its anti‑inflammatory activity on concanavalin A (Con A)-induced hepatitis remains unknown. The aim of the present study was to investigate the protective effects of PD1 against Con A‑induced liver injury and the underlying mechanisms via intravenous injection of PD1 prior to Con A administration. C57BL/6 mice were randomly divided into four experimental groups as follows: Control group, Con A group (30 mg/kg), 20 µg/kg PD1 + Con A (30 mg/kg) group and 10 µg/kg PD1 + Con A (30 mg/kg) group...
April 2016: Molecular Medicine Reports
B Levi, P Matzner, Y Goldfarb, L Sorski, L Shaashua, R Melamed, E Rosenne, G G Page, S Ben-Eliyahu
We recently reported that immune stimulation can be compromised if animals are simultaneously subjected to stressful conditions. To test the generalizability of these findings, and to elucidate neuroendocrine mediating mechanisms, we herein employed CpG-C, a novel TLR-9 immune-stimulating agent. Animals were subjected to ongoing stress (20-h of wet cage exposure) during CpG-C treatment, and antagonists to glucocorticoids, β-adrenoceptor, COX2, or opioids were employed (RU486, nadolol, etodolac, naltrexone)...
August 2016: Brain, Behavior, and Immunity
Y Poorna Chandra Rao, P Pavan Kumar, B R Lokesh
Industrially produced partially hydrogenated vegetable fat (PHVF) contains trans fatty acids (TFA) mostly comprising elaidic acid (EA, 18:1∆9t). Though, the harmful effects of TFA on health have been repeatedly publicized, the fat containing TFA have been continued to be used as a cooking medium in many regions of the world. The adverse effects of PHVF on oxidative stress and inflammatory markers and the possible ameliorative action of rice bran oil (RBO) on these markers were evaluated. Weaning rats were fed a AIN-93 purified diet supplemented with the following lipids: groundnut oil (GNO, 10 wt%), PHVF (10 wt%), RBO (10 wt%), PHVF blended with RBO at 2...
April 2016: Lipids
Dandan Yu, Yong Wu, Ling Xu, Yu Fan, Li Peng, Min Xu, Yong-Gang Yao
In mammals, the toll-like receptors (TLRs) play a major role in initiating innate immune responses against pathogens. Comparison of the TLRs in different mammals may help in understanding the TLR-mediated responses and developing of animal models and efficient therapeutic measures for infectious diseases. The Chinese tree shrew (Tupaia belangeri chinensis), a small mammal with a close relationship to primates, is a viable experimental animal for studying viral and bacterial infections. In this study, we characterized the TLRs genes (tTLRs) in the Chinese tree shrew and identified 13 putative TLRs, which are orthologs of mammalian TLR1-TLR9 and TLR11-TLR13, and TLR10 was a pseudogene in tree shrew...
July 2016: Developmental and Comparative Immunology
M M Mina, B Cameron, F Luciani, U Vollmer-Conna, A R Lloyd
Injecting drug use remains the major risk factor for hepatitis C (HCV) transmission. A minority of long-term injecting drug users remain seronegative and aviraemic, despite prolonged exposure to HCV - termed highly exposed seronegative subjects. Natural killer (NK) cells have been implicated in this apparent protection. A longitudinal nested, three group case-control series of subjects was selected from a prospective cohort of seronegative injecting drug users who became incident cases (n = 11), remained seronegative (n = 11) or reported transient high-risk behaviour and remained uninfected (n = 11)...
June 2016: Journal of Viral Hepatitis
M L Moraes, A M L Ribeiro, E Santin, K C Klasing
The effects of lutein and conjugated linoleic acid (CLA) on growth performance and immune response of broiler chickens were evaluated in the presence and absence of Salmonella lipopolysaccharide (LPS) immune challenge. Cobb chicks (360; 1 to 22 d of age) were used in a 3 × 2 factorial arrangement of CLA (0, 1, and 2%) and lutein (0 and 50 mg/kg) dietary levels. At d 8 and 15, birds were injected with BSA to assess IgY production. At d 20, birds were injected with LPS. Samples of liver, spleen, and duodenum were collected at 3 and 16 h post-LPS challenge for RT-qPCR analysis of RXRα, RXRγ, PPARα, PPARγ, TLR-4, IL-1β, IL-2, IL-10, and IL-12 gene expression...
February 2016: Poultry Science
Weihong Sun, Xiaofang Wei, Peng Zhao, Airong Niu, Changyou Li, Daiqing Gao
OBJECTIVE: To investigate the mechanisms underlying the ability ofheparin-treated dendritic cells (DCs) to promote Th0 to Th1 differentiation in chronic hepatitis B (CHB). METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from CHB patients and cultured in RPMI-1640 with recombinant GM-CSF and IL-4 with or without heparin to obtain DCs for study. The levels of Toll-like receptors (TLRs) on the DCs were measured using FACS and qPCR techniques.DC subsets with high expression of TLRs were selected for analysis of functional changes by treatment with the corresponding TLR-siRNA...
September 2015: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
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