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Mei TTY, Aung HH, Tung WS, Naing C. Association between IL-10 gene polymorphisms (- 1082 A/G, -819 T/C, -592 A/C) and hepatocellular carcinoma: a meta-analysis and trial sequential analysis. BMC Cancer 2023; 23:842. [PMID: 37684564 PMCID: PMC10492326 DOI: 10.1186/s12885-023-11323-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
BACKGROUND The carcinogenesis of hepatocellular carcinoma is complicated, and genetic factor may have the role in the malignant transformation of liver cells. IL-10 gene polymorphisms have been investigated for their potential roles in hepatocellular carcinoma This study aimed to investigate the relationship between polymorphisms of IL-10 (-1082 A/G, -819 T/C, -592 A/C), and hepatocellular carcinoma by performing a meta-analysis with eligible individual studies. METHODS This study followed the PRISMA 2020 Checklist. Relevant studies were searched in health-related databases. The Newcastle-Ottawa Scale criteria were used to evaluate the studies quality. Pooled odds ratio (OR) and its 95% confidence interval (CI) were used to determine the strength of association between each polymorphism and hepatocellular carcinoma using five genetic models. Stratification was done by ethnic groups. Trial sequential analysis (TSA) was performed to determine the required information size. RESULTS Fifteen case-control studies (n = 8182) were identified. Overall, the heterozygous model showed a marginal significant association only between IL-10 (-1082 A/G) and hepatocellular carcinoma risk (OR: 0.82, 95% CI: 0.67-1.00, 9 studies). On stratification, IL-10 (-1082 A/G) was significantly associated with hepatocellular carcinoma risk in the non-Asian population under dominant (OR: 0.62, 95% CI: 0.45-0.86, 4 studies), heterozygous (OR: 0.60, 95% CI: 0.43-0.85) and allelic models (OR: 0.79, 95% CI: 0.64-0.99). IL-10 (-819 T/C) was significantly associated with hepatocellular carcinoma risk only among non-Asians under the dominant (OR: 1.47, 95% CI: 1.02-2.13, 8 studies), recessive (OR: 1.99, 95% CI: 1.03-3.86, and homozygous models (OR: 2.18, 95% CI: 1.13-4.23). For IL-10 (-592 A/C) with 11 studies, there was no significant association with hepatocellular carcinoma in all five genetic models (P values > 0.5). TSA plots indicated that the information size for firm evidence of effect was sufficient only for the analysis of IL-10 (-592 A/C), but not for the - 1082 A/G or -819 T/C. CONCLUSIONS Findings suggest that IL-10 (-1082 A/G and - 819 T/C) polymorphisms are associated with hepatocellular carcinoma in ethnic-specific manner. However, this evidence is not conclusive because the sample size was insufficient. IL-10 (-592 A/C) polymorphism was not associated with hepatocellular carcinoma albeit with sufficient information size. Future well-designed large case-control studies on IL-10 (-1082 A/G and - 819 T/C) with different ethnicities are recommended.
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Affiliation(s)
- Teresa Tan Yen Mei
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
- School of Medicine, University of Adelaide, Adelaide, Australia
| | - Htar Htar Aung
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia.
| | - Wong Siew Tung
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Cho Naing
- Faculty of Tropical Health and Medicine, James Cook University, Queensland, Australia
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Lara-Aguilar V, Crespo-Bermejo C, Llamas-Adán M, Grande-García S, Cortijo-Alfonso ME, Martín-Carbonero L, Domínguez L, Ryan P, de Los Santos I, Bartolomé-Sanchez S, Valle-Millares D, Jiménez-Sousa MÁ, Briz V, Fernández-Rodríguez A. HCV spontaneous clearers showed low senescence profile in people living with HIV under long ART. J Med Virol 2023; 95:e28955. [PMID: 37465865 DOI: 10.1002/jmv.28955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/30/2023] [Accepted: 06/29/2023] [Indexed: 07/20/2023]
Abstract
Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) increases immune activation, inflammation, and oxidative stress that could lead to premature senescence. Different HCV infections, either acute or chronic infection, could lead to distinct premature cellular senescence in people living with HIV (PLWHIV). Observational study in 116 PLWHIV under antiretroviral treatment with different HCV status: (i) n = 45 chronically infected with HCV (CHC); (ii) n = 36 individuals who spontaneously clarify HCV (SC); (iii) n = 35 HIV controls. Oxidative stress biomarkers were analyzed at lipid, DNA, protein, and nitrates levels, as well as antioxidant capacity and glutathione reductase enzyme. Replicative senescence was evaluated by relative telomere length (RTL) measurement. Additionally, 26 markers of Senescence-Associated Secretory Phenotype (SASP) were analyzed by multiplex immunoassays (Luminex xMAP technology). Differences were evaluated by generalized linear model (GLMs) adjusted by most significant covariates. The SC group had a senescence signature similar to the HIV control group and slightly lower SASP levels. However, significant differences were observed with respect to the CHC group, where an increase in the nitrate concentration [adjusted arithmetic mean ratio, aAMR = 1.73 (1.27-2.35), p < 0.001, q = 0.009] and the secretion of 13 SASP-associated factors [granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-β, interleukin (IL)-1β, IL-2, IL-8, IL-13, tumor necrosis factor (TNF)-α, IL-1α, IL-1RA, IL-7, IL-15, C-X-C motif chemokine ligand 10 (IP-10), stem cell factor (SCF); q < 0.1)] was detected. The CHC group also showed higher values of IL-1α, IP-10, and placental growth factor 1 (PIGF-1) than HIV controls. The SC group showed a slightly lower senescence profile than the HIV group, which could indicate a more efficient control of viral-induced senescence due to their immune strengths. Chronic HCV infection in PLWHIV led to an increase in nitrate and elevated SASP biomarkers favoring the establishment of viral persistence.
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Affiliation(s)
- Violeta Lara-Aguilar
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - Celia Crespo-Bermejo
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - Manuel Llamas-Adán
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - Sergio Grande-García
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - María Engracia Cortijo-Alfonso
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | | | - Lourdes Domínguez
- VIH Unit, Internal Medicine Service, Doce de Octubre Hospital Biomedical Research Institute (imas12), Madrid, Spain
- King's College London University, London, UK
| | - Pablo Ryan
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Institute of Health Carlos III, Madrid, Spain
- Department of Infectious Diseases, HIV/Hepatitis Internal Medicine Service, Infanta Leonor University Hospital, Madrid, España
| | - Ignacio de Los Santos
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Institute of Health Carlos III, Madrid, Spain
- Internal Medicine-Infectious Diseases Service, La Princesa University Hospital, Madrid, España
| | - Sofía Bartolomé-Sanchez
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - Daniel Valle-Millares
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - María Ángeles Jiménez-Sousa
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Institute of Health Carlos III, Madrid, Spain
| | - Verónica Briz
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - Amanda Fernández-Rodríguez
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Institute of Health Carlos III, Madrid, Spain
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Morrow JD, Castaldi PJ, Chase RP, Yun JH, Kinney GL, Silverman EK, Hersh CP. Hepatitis C and HIV detection by blood RNA-sequencing in cohort of smokers. Sci Rep 2023; 13:1357. [PMID: 36693932 PMCID: PMC9873751 DOI: 10.1038/s41598-023-28156-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 01/13/2023] [Indexed: 01/26/2023] Open
Abstract
Detection of viruses by RNA and DNA sequencing has improved the understanding of the human virome. We sought to identify blood viral signatures through secondary use of RNA-sequencing (RNA-seq) data in a large study cohort. The ability to reveal undiagnosed infections with public health implications among study subjects with available sequencing data could enable epidemiologic surveys and may lead to diagnosis and therapeutic interventions, leveraging existing research data in a clinical context. We detected viral RNA in peripheral blood RNA-seq data from a COPD-enriched population of current and former smokers. Correlation between viral detection and both reported infections and relevant disease outcomes was evaluated. We identified Hepatitis C virus RNA in 228 subjects and HIV RNA in 30 subjects. Overall, we observed 31 viral species, including Epstein-Barr virus and Cytomegalovirus. We observed an enrichment of Hepatitis C and HIV infections among subjects reporting liver disease and HIV infections, respectively. Higher interferon expression scores were observed in the subjects with Hepatitis C and HIV infections. Through secondary use of RNA-seq from a cohort of current and former smokers, we detected peripheral blood viral signatures. We identified HIV and Hepatitis C virus (HCV), highlighting potential public health implications for the approach described this study. We observed correlations with reported infections, chronic infection outcomes and the host transcriptomic response, providing evidence to support the validity of the approach.
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Affiliation(s)
- Jarrett D Morrow
- Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA.
| | - Peter J Castaldi
- Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Robert P Chase
- Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA
| | - Jeong H Yun
- Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Gregory L Kinney
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Edwin K Silverman
- Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Craig P Hersh
- Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA
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Liu Y, Dong Y, Wu X, Wang X, Niu J. Identification of Immune Microenvironment Changes and the Expression of Immune-Related Genes in Liver Cirrhosis. Front Immunol 2022; 13:918445. [PMID: 35903097 PMCID: PMC9315064 DOI: 10.3389/fimmu.2022.918445] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Liver inflammation and the immune response have been recognized as critical contributors to cirrhosis pathogenesis. Immunity-related genes (IRGs) play an essential role in immune cell infiltration and immune reactions; however, the changes in the immune microenvironment and the expression of IRGs involved in cirrhosis remain unclear. CD45+ liver cell single-cell RNA (scRNA) sequencing data (GSE136103) from patients with cirrhosis were analyzed. The clusters were identified as known cell types through marker genes according to previous studies. GO and KEGG analyses among differentially expressed genes (DEGs) were performed. DEGs were screened to identify IRGs based on the ImmPort database. The protein-protein interaction (PPI) network of IRGs was generated using the STRING database. IRGs activity was calculated using the AUCell package. RNA microarray expression data (GSE45050) of cirrhosis were analyzed to confirm common IRGs and IRGs activity. Relevant regulatory transcription factors (TFs) were identified from the Human TFDB database. A total of ten clusters were obtained. CD8+ T cells and NK cells were significantly decreased in patients with cirrhosis, while CD4+ T memory cells were increased. Enrichment analyses showed that the DEGs focused on the regulation of immune cell activation and differentiation, NK-cell mediated cytotoxicity, and antigen processing and presentation. Four common TFs, IRF8, NR4A2, IKZF3, and REL were expressed in both the NK cluster and the DEGs of liver tissues. In conclusion, we proposed that the reduction of the CD8+ T cell cluster and NK cells, as well as the infiltration of CD4+ memory T cells, contributed to immune microenvironment changes in cirrhosis. IRF8, NR4A2, IKZF3, and REL may be involved in the transcriptional regulation of NK cells in liver fibrosis. The identified DEGs, IRGs, and pathways may serve critical roles in the development and progression of liver fibrosis.
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Affiliation(s)
- Yuwei Liu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Organ Transplantation, Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Yutong Dong
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Organ Transplantation, Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Xiaojing Wu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Organ Transplantation, Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Xiaomei Wang
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Organ Transplantation, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Junqi Niu, ; Xiaomei Wang,
| | - Junqi Niu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Organ Transplantation, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Junqi Niu, ; Xiaomei Wang,
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Rossi C, Salvati A, Distaso M, Campani D, Raggi F, Biancalana E, Tricò D, Brunetto MR, Solini A. The P2X7R-NLRP3 and AIM2 Inflammasome Platforms Mark the Complexity/Severity of Viral or Metabolic Liver Damage. Int J Mol Sci 2022; 23:ijms23137447. [PMID: 35806450 PMCID: PMC9267345 DOI: 10.3390/ijms23137447] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 06/26/2022] [Accepted: 06/30/2022] [Indexed: 12/03/2022] Open
Abstract
P2X7R-NLRP3 and AIM2 inflammasomes activate caspase-1 and the release of cytokines involved in viral-related liver disease. Little is known about their role in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steato-hepatitis (NASH). We characterized the role of inflammasomes in NAFLD, NASH, and HCV. Gene expression and subcellular localization of P2X7R/P2X4R-NLRP3 and AIM2 inflammasome components were examined in histopathological preparations of 46 patients with biopsy-proven viral and metabolic liver disease using real-time PCR and immunofluorescence. P2X7R, P2X4R, and Caspase-1 are two- to five-fold more expressed in patients with NAFLD/NASH associated with chronic HCV infection than those with metabolic damage only (p ≤ 0.01 for all comparisons). The AIM2 inflammasome is 4.4 times more expressed in patients with chronic HCV infection, regardless of coexistent metabolic abnormalities (p = 0.0006). IL-2, a cytokine playing a pivotal role during chronic HCV infection, showed a similar expression in HCV and NASH patients (p = 0.77) but was virtually absent in NAFLD. The P2X7R-NLRP3 complex prevailed in infiltrating macrophages, while AIM2 was localized in Kupffer cells. Caspase-1 expression correlated with elastography-based liver fibrosis (r = 0.35, p = 0.02), whereas P2X7R, P2X4R, NRLP3, Caspase-1, and IL-2 expression correlated with circulating markers of disease severity. P2X7R and P2X4R play a major role in liver inflammation accompanying chronic HCV infection, especially when combined with metabolic damage, while AIM2 is specifically expressed in chronic viral hepatitis. We describe for the first time the hepatic expression of IL-2 in NASH, so far considered a peculiarity of HCV-related liver damage.
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Affiliation(s)
- Chiara Rossi
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (C.R.); (M.D.); (F.R.)
| | - Antonio Salvati
- Azienda Ospedaliero-Universitaria Pisana, I-56126 Pisa, Italy;
| | - Mariarosaria Distaso
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (C.R.); (M.D.); (F.R.)
| | - Daniela Campani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, I-56126 Pisa, Italy;
| | - Francesco Raggi
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (C.R.); (M.D.); (F.R.)
| | - Edoardo Biancalana
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (E.B.); (D.T.)
| | - Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (E.B.); (D.T.)
| | - Maurizia Rossana Brunetto
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (E.B.); (D.T.)
- Correspondence: (M.R.B.); (A.S.); Tel.: +39-050-996857 (M.R.B.); +39-050-993482 (A.S.); Fax: +39-050-553235 (A.S.)
| | - Anna Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (C.R.); (M.D.); (F.R.)
- Correspondence: (M.R.B.); (A.S.); Tel.: +39-050-996857 (M.R.B.); +39-050-993482 (A.S.); Fax: +39-050-553235 (A.S.)
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Cytokine (IL-10, IL-6, TNF-α and TGF-β1) Gene Polymorphisms in Chronic Hepatitis C Virus Infection among Malay Male Drug Abusers. Biomedicines 2021; 9:biomedicines9091115. [PMID: 34572300 PMCID: PMC8469205 DOI: 10.3390/biomedicines9091115] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/24/2021] [Accepted: 08/28/2021] [Indexed: 11/17/2022] Open
Abstract
Cytokines play an important role in modulating inflammation during viral infection, including hepatitis C virus (HCV) infection. Genetic polymorphisms of cytokines can alter the immune response against this infection. The objective of this study was to investigate the possible association between chronic hepatitis C virus infection susceptibility and cytokine gene polymorphism for interleukin-10 (IL-10) rs1800896 and rs1800871, interleukin 6 (IL-6) rs1800795, TNF-α rs1800629, and TGF-β1 rs1800471 in Malay male drug abusers. The study was conducted on 76 HCV-positive (HP) male drug abusers and 40 controls (HCV-negative male drug abusers). We found that there were significant differences in the frequencies of genotype for IL-10 rs1800871 (p = 0.0386) and at the allelic level for IL-10 rs1800896 A versus G allele (p = 0.0142) between the HP group and the control group. However, there were no significant differences in gene polymorphism in interleukin 6 rs1800795, TNF-α rs1800629 and TGF-β1 rs1800471. These findings suggest significant associations between gene polymorphism for IL-10 rs1800871, IL-10 rs1800896 (at the allelic level) and susceptibility to HCV infection among Malay male drug abusers.
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Abstract
Hepatic fibrosis is a complex mechanism defined by the net deposition of the extracellular matrix (ECM) owing to liver injury caused by multiple etiologies such as viral hepatitis and nonalcoholic fatty liver disease. Many cell types are implicated in liver fibrosis development and progression. In general, liver fibrosis starts with the recruitment of inflammatory immune cells to generate cytokines, growth factors, and other activator molecules. Such chemical mediators drive the hepatic stellate cells (HSCs) to activate the production of the ECM component. The activation of HSC is thus a crucial event in the fibrosis initiation, and a significant contributor to collagen deposition (specifically type I). This review explores the causes and mechanisms of hepatic fibrosis and focuses on the roles of key molecules involved in liver fibro genesis, some of which are potential targets for therapeutics to hamper liver fibro genesis.
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Affiliation(s)
- Reham M Dawood
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mai A El-Meguid
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Ghada Maher Salum
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mostafa K El Awady
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
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Cheng W, Meng W, Gu Y. Metalloprotease Adam10 inhibition mitigates acute liver injury via repression of intrahepatic inflammation. Minerva Med 2020; 113:506-512. [PMID: 32512977 DOI: 10.23736/s0026-4806.20.06655-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Acute liver injury (ALI) is associated with the occurrence and progress of intrahepatic inflammation. Recent studies have shown that Adam10, a significant member of metalloproteinase family, has modulated the inflammation level in various neurologic diseases. However, it is elusive whether Adam10 regulation exert a hepatic protective effect on ALI by the suppression of inflammation level. The study aimed to explore the regulated function of Adam10 on acute liver injury. METHODS C57BL/6J mice (eight-week-old, male) were carried out intraperitoneal injection of tetrachloromethane (CTC) to provoke ALI. Adam 10 loaded in Adeno-associated viral vectors (AAV-Adam 10) or short hairpin RNA loaded in lentivirus aimed at murine Adam 10 mRNA (sh-RNA-Adam 10) were respectively delivered to mice via tail intravenous injection to achieve overexpression or silence of Adam 10. Western blotting, reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), immumohistochemical (IHC) and hematoxylin and eosin (HE) staining were conducted to measure Adam 10 alteration, inflammation level, histology and liver function. RESULTS We show that the expression of Adam 10 markedly increases in CTC-induced injured liver tissues. Moreover, we demonstrate that the knockdown of Adam 10 attenuates the intrahepatic inflammation and protects hepatic histology and function in ALI mice, however the overexpression of Adam10 aggravates inflammation and liver lesion. CONCLUSIONS The above suggested that the inhibition of Adam 10 ameliorates ALI through inhibiting inflammation. Our research provides novel view on the Adam 10 modulation of process of ALI by the inflammation aspect and verify a potential target for the therapy of ALI in the future.
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Affiliation(s)
- Weihua Cheng
- Departments of Hepatobiliary, Pancreatic and Splenic Surgery, Baoji Central Hospital, Baoji, China
| | - Wei Meng
- Department of Infectious Disease, Binzhou People's Hospital, Binzhou, China
| | - Yihai Gu
- Department of Traditional Chinese Medicine, Sixth People's Hospital of Qingdao, Qingdao, China -
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Abstract
The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body's immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.
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Di Minno MND, Ambrosino P, Buonomo AR, Pinchera B, Calcaterra I, Crispo M, Scotto R, Borgia F, Mattia C, Gentile I. Direct-acting antivirals improve endothelial function in patients with chronic hepatitis: a prospective cohort study. Intern Emerg Med 2020; 15:263-271. [PMID: 31396919 DOI: 10.1007/s11739-019-02163-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 07/27/2019] [Indexed: 12/21/2022]
Abstract
Hepatitis C virus (HCV) infection is associated with increased cardiovascular risk. We evaluated effects of direct-acting antiviral agents (DAAs) on flow-mediated dilation (FMD), a recognized marker of cardiovascular risk. We evaluated FMD and post-ischemic hyperemia (PIH) in consecutive HCV out-patients before starting DAAs, at the end of treatment (Teot) and 12 weeks thereafter. In 22 HCV subjects (age 64.0 years), baseline FMD was 4.52% ± 1.90 and PIH of 5814.4 (IQR 3786.9-7861.9). At (Teot), all patients showed undetectable levels of HCV-RNA and FMD changed from 4.52% ± 1.90 to 9.39% ± 4.06 (p < 0.001), with a direct correlation between changes in FMD and baseline HCV-RNA levels (r = 0.494, p = 0.020). In parallel, PIH increased from 5814.4 (IQR 3786.9-7861.9) to 7277.6 (IQR 4579.8-10388.8) (p = 0.019). Twelve weeks after Teot, all patients had persistently negative HCV-RNA, FMD was 10.9% ± 4.65 and PIH was 10930.3 (IQR 6254.6-18248.2) suggesting a further significant improvement in these parameters. Results remained significant regardless of the presence of cardiovascular risk factors, whereas FMD changes were not statistically significant in subjects with cirrhosis. A persistent and significant improvement in endothelial function is observed in HCV patients obtaining viral eradication with DAAs treatment. This might suggest a beneficial effect of DAAs treatment on cardiovascular risk profile of HCV patients.
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Affiliation(s)
| | - Pasquale Ambrosino
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | | | - Biagio Pinchera
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Ilenia Calcaterra
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Manuel Crispo
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Riccardo Scotto
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Francesco Borgia
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Consalvo Mattia
- Department of Medical and Surgical Sciences and Biotechnologies, Unit of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Faculty of Pharmacy and Medicine, "Polo Pontino", "Sapienza" University of Rome, Rome, Italy
| | - Ivan Gentile
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
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11
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Ouaguia L, Moralès O, Aoudjehane L, Wychowski C, Kumar A, Dubuisson J, Calmus Y, Conti F, Delhem N. Hepatitis C Virus Improves Human Tregs Suppressive Function and Promotes Their Recruitment to the Liver. Cells 2019; 8:cells8101296. [PMID: 31652598 PMCID: PMC6829901 DOI: 10.3390/cells8101296] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 10/09/2019] [Accepted: 10/10/2019] [Indexed: 12/31/2022] Open
Abstract
Background: The role of regulatory T cells (Tregs) is now well established in the progression of hepatocellular carcinoma (HCC) linked to Hepatitis C virus (HCV) infection. However, nothing is known about the potential interplay between Tregs and HCV. In this pilot study, we have investigated the ability of Tregs to hang HCV on and the subsequent effect on their suppressive function and phenotype. Moreover, we have evaluated how HCV could promote the recruitment of Tregs by infected primary human hepatocytes. Methods: Tregs of healthy donors were incubated with JFH-1/HCVcc. Viral inoculation was assessed using adapted assays (RT-qPCR, Flow Citometry (FACS) and Western Blot (WB). Expression of Tregs phenotypic (CD4, CD25, CD127 and Foxp3) and functional (IL-10, GZMB, TGF-β1 and IL-2) markers was monitored by RT-qPCR, FACS and ELISA. Suppressive activity was validated by suppressive assays. Tregs recruitment by infected primary hepatic cells was evaluated using Boyden Chamber. Results: Tregs express the classical HCV receptors (CD81, CLDN1 and LDLR) and some co-receptors (CD5). HCV inoculation significantly increases the suppressive phenotype and activity of Tregs, and raises their anergy by inducing an unexpected IL-2 production. Moreover, HCV infection induces the expression of chemokines (CCL17, CXCL16, and CCL20) by primary hepatic human hepatocytes and chemokine receptors (CCR4, CXCR6 and CCR6) by Tregs. Finally, infected hepatocytes have a significantly higher potential to recruit Tregs in a seemingly CCL20-dependent manner. Conclusions: Direct interaction between HCV and Tregs represents a newly defined mechanism that could potentiate HCV immune evasion and favor intratumoral recruitment contributing to HCC progression.
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Affiliation(s)
- Laurissa Ouaguia
- Université Lille, UMR 8161-M3T-Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
- CNRS-UMR 8161, F-59000 Lille, France.
- Institut Pasteur de Lille, F-59000 Lille, France.
| | - Olivier Moralès
- Université Lille, UMR 8161-M3T-Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
- CNRS-UMR 8161, F-59000 Lille, France.
- Institut Pasteur de Lille, F-59000 Lille, France.
| | - Lynda Aoudjehane
- Sorbonne Université, INSERM, Institute of Cardiometabolism and Nutrition (ICAN), F-75013 Paris, France.
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), F-75012 Paris, France.
| | - Czeslaw Wychowski
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
| | - Abhishek Kumar
- Université Lille, UMR 8161-M3T-Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
- CNRS-UMR 8161, F-59000 Lille, France.
- Institut Pasteur de Lille, F-59000 Lille, France.
| | - Jean Dubuisson
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
| | - Yvon Calmus
- Sorbonne Université, INSERM, Institute of Cardiometabolism and Nutrition (ICAN), F-75013 Paris, France.
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), F-75012 Paris, France.
- Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Department of Medical Liver Transplantation, F-75013 Paris, France.
| | - Filomena Conti
- Sorbonne Université, INSERM, Institute of Cardiometabolism and Nutrition (ICAN), F-75013 Paris, France.
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), F-75012 Paris, France.
- Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Department of Medical Liver Transplantation, F-75013 Paris, France.
| | - Nadira Delhem
- Université Lille, UMR 8161-M3T-Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
- CNRS-UMR 8161, F-59000 Lille, France.
- Institut Pasteur de Lille, F-59000 Lille, France.
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12
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Liu Y, Liu H, Zhu J, Bian Z. Interleukin-34 drives macrophage polarization to the M2 phenotype in autoimmune hepatitis. Pathol Res Pract 2019; 215:152493. [DOI: 10.1016/j.prp.2019.152493] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 05/22/2019] [Accepted: 06/08/2019] [Indexed: 01/16/2023]
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13
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Ahmed F, Ibrahim A, Cooper CL, Kumar A, Crawley AM. Chronic Hepatitis C Virus Infection Impairs M1 Macrophage Differentiation and Contributes to CD8 + T-Cell Dysfunction. Cells 2019; 8:E374. [PMID: 31027182 PMCID: PMC6523920 DOI: 10.3390/cells8040374] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 04/15/2019] [Accepted: 04/18/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection causes generalized CD8+ T cell impairment, not limited to HCV-specific CD8+ T-cells. Liver-infiltrating monocyte-derived macrophages (MDMs) contribute to the local micro-environment and can interact with and influence cells routinely trafficking through the liver, including CD8+ T-cells. MDMs can be polarized into M1 (classically activated) and M2a, M2b, and M2c (alternatively activated) phenotypes that perform pro- and anti-inflammatory functions, respectively. The impact of chronic HCV infection on MDM subset functions is not known. Our results show that M1 cells generated from chronic HCV patients acquire M2 characteristics, such as increased CD86 expression and IL-10 secretion, compared to uninfected controls. In contrast, M2 subsets from HCV-infected individuals acquired M1-like features by secreting more IL-12 and IFN-γ. The severity of liver disease was also associated with altered macrophage subset differentiation. In co-cultures with autologous CD8+ T-cells from controls, M1 macrophages alone significantly increased CD8+ T cell IFN-γ expression in a cytokine-independent and cell-contact-dependent manner. However, M1 macrophages from HCV-infected individuals significantly decreased IFN-γ expression in CD8+ T-cells. Therefore, altered M1 macrophage differentiation in chronic HCV infection may contribute to observed CD8+ T-cell dysfunction. Understanding the immunological perturbations in chronic HCV infection will lead to the identification of therapeutic targets to restore immune function in HCV+ individuals, and aid in the mitigation of associated negative clinical outcomes.
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Affiliation(s)
- Faria Ahmed
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
| | - Andrea Ibrahim
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
| | - Curtis L Cooper
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
- Department of Medicine, Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada.
- Public Health and Preventative Medicine, School of Epidemiology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1G 5Z3, Canada.
| | - Ashok Kumar
- Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
- Department of Pathology, The Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.
| | - Angela M Crawley
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
- Department of Medicine, Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada.
- Department of Biology, Faculty of Science, Carleton University, Ottawa, ON K1S 5B6, Canada.
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14
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Mansour HM, Salama AAA, Abdel-Salam RM, Ahmed NA, Yassen NN, Zaki HF. The anti-inflammatory and anti-fibrotic effects of tadalafil in thioacetamide-induced liver fibrosis in rats. Can J Physiol Pharmacol 2018; 96:1308-1317. [PMID: 30398909 DOI: 10.1139/cjpp-2018-0338] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. This study aimed to explore the protective effect of tadalafil, a phosphodiesterase-5 inhibitor, against thioacetamide (TAA)-induced liver fibrosis. Fibrosis was induced by administration of TAA (200 mg/kg, i.p.) twice weekly for 6 weeks. Serum transaminases activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA induced marked histopathological changes in liver tissues coupled with elevations in serum transaminases activities. Furthermore, hepatic content of nitric oxide and tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta were elevated, together with a reduction of interleukin-10 in the liver. In addition, TAA increased hepatic contents of transforming growth factor-beta, hydroxyproline, alpha-smooth muscle actin, and gene expression of collagen-1. Pretreatment with tadalafil protected against TAA-induced liver fibrosis, in a dose-dependent manner, as proved by the alleviation of inflammatory and fibrotic biomarkers. The effects of tadalafil were comparable with that of silymarin, a natural antioxidant, and could be assigned to its anti-inflammatory and anti-fibrotic properties.
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Affiliation(s)
- Heba M Mansour
- a Pharmacology & Toxicology Department, Faculty of Pharmacy, Misr University for Science and Technology, Giza, Egypt
| | - Abeer A A Salama
- b Pharmacology Department, National Research Centre, Giza, Egypt
| | - Rania M Abdel-Salam
- c Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Naglaa A Ahmed
- a Pharmacology & Toxicology Department, Faculty of Pharmacy, Misr University for Science and Technology, Giza, Egypt
| | - Noha N Yassen
- d Pathology Department, National Research Centre, Giza, Egypt
| | - Hala F Zaki
- c Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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15
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Ma K, Ma P, Lu H, Liu S, Cao Q. Fentanyl Suppresses the Survival of CD4+T Cells Isolated from Human Umbilical Cord Blood through Inhibition of IKKs-mediated NF-κB Activation. Scand J Immunol 2017; 85:343-349. [PMID: 28199730 DOI: 10.1111/sji.12538] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 02/09/2017] [Indexed: 11/29/2022]
Affiliation(s)
- K. Ma
- Department of Anesthesiology; The Fourth Hospital of Shijiazhuang; Shijiazhuang China
| | - P. Ma
- Department of Anesthesiology; The First Hospital of Shijiazhuang; Shijiazhuang China
| | - H. Lu
- ICU; The Second Hospital of Hebei Medical University; Shijiazhuang China
| | - S. Liu
- Department of Anesthesiology; The Fourth Hospital of Shijiazhuang; Shijiazhuang China
| | - Q. Cao
- The Fourth Hospital of Shijiazhuang; Shijiazhuang China
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16
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Mehta M, Hetta HF, Abdel-Hameed EA, Rouster SD, Hossain M, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, El-Mokhtar MA, Abdelwahab SF, Medhat A, Sherman KE, Shata MTM. Association between IL28B rs12979860 single nucleotide polymorphism and the frequency of colonic Treg in chronically HCV-infected patients. Arch Virol 2016; 161:3161-9. [PMID: 27544760 PMCID: PMC5035222 DOI: 10.1007/s00705-016-3015-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 08/11/2016] [Indexed: 02/08/2023]
Abstract
The IL28B gene is associated with spontaneous or treatment-induced HCV viral clearance. However, the mechanism by which the IL28B single nucleotide polymorphism (SNP) affects the extra-hepatic HCV immune responses and its relationship to HCV pathogenesis have not been thoroughly investigated. To examine the mechanism by which IL28B affects HCV clearance. Forty Egyptian patients with chronic HCV infection receiving an Interferon/ribavirin treatment regimen were enrolled into this study. There were two groups: non-responders (NR; n = 20) and sustained virologic responders (SVR; n = 20). The initial plasma HCV viral loads prior to treatment and IL28B genotypes were determined by quantitative RT-PCR and sequencing, respectively. Liver biopsies were examined to determine the inflammatory score and the stage of fibrosis. Colonic regulatory T cell (Treg) frequency was estimated by immunohistochemistry. No significant association between IL28B genotypes and response to therapy was identified, despite an odds ratio of 3.4 to have the TT genotype in NR compared to SVR (95 % confidence interval 0.3-35.3, p = 0.3). Patients with the TT-IL28Brs12979860 genotype (unfavorable genotype) have significantly higher frequencies of colonic Treg compared to the CT (p = 0.04) and CC (p = 0.03) genotypes. The frequency of colonic Treg cells in HCV-infected patients had a strong association with the IL-28B genotype and may have a significant impact on HCV clearance.
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Affiliation(s)
- Minesh Mehta
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA
| | - Helal F Hetta
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Enass A Abdel-Hameed
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA
| | - Susan D Rouster
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA
| | - MdMonir Hossain
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Mohamed A Mekky
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nasr K Khalil
- Assiut Liver Institute for Treatment of Hepatitis C, Assiut, Egypt
| | - Wegdan A Mohamed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Feky
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Shabaan H Ahmed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Enas A Daef
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Sayed F Abdelwahab
- Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minya, Egypt
| | - Ahmed Medhat
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Kenneth E Sherman
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA
| | - Mohamed Tarek M Shata
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA.
- Department of Microbiology, Saint James School of Medicine, Saint Vincent, Arnos Vale, Saint Vincent and the Grenadines.
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17
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Pateria P, Jeffrey GP, MacQuillan G, Speers D, Ching H, Chinnaratha MA, Watts GF, Adams LA. The association between chronic hepatitis C infection and cardiovascular risk. Intern Med J 2016; 46:63-70. [PMID: 26477784 DOI: 10.1111/imj.12936] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 09/29/2015] [Accepted: 10/10/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Vascular disease is a common cause of death in patients with chronic hepatitis C (CHC) infection; however, the association between CHC and atherosclerosis is unclear. AIMS To determine whether patients with CHC have increased subclinical vascular disease and whether genotype or antiviral treatment modifies this risk. METHODS Fifty CHC patients and 22 age-matched and sex-matched healthy controls underwent clinical and biochemical assessment for vascular risk factors. In addition, vascular risk was assessed by measuring arterial stiffness (aortic augmentation index and carotid-femoral pulse wave velocity (PWV)), endothelial dysfunction (brachial artery flow-mediated dilatation (FMD) and dilatation post-glycerol trinitrate administration) and carotid intima-media thickness (CIMT). Assessment was repeated in subset of CHC patients (n = 12) undergoing antiviral treatment 18 months after initiation of treatment. RESULTS Baseline vascular risk factors and measures of arterial stiffness, endothelial dysfunction and CIMT were not different between cases and controls (P > 0.2 for all). Genotype 1 CHC patients had greater endothelial dysfunction with lower FMD (8.2 ± 3.5% vs 10.9 ± 5.2%, P = 0.03) and higher right CIMT (0.6 ± 0.1 mm vs 0.5 ± 0.07 mm, P = 0.04) compared with non-genotype 1. Patients who achieved sustained virological response (7/12) showed significant improvement in insulin resistance (homeostasis model of assessment of insulin resistance 2.3 ± 1.2 vs 1.8 ± 0.8, P = 0.02) and arterial stiffness (PWV 7.4 ± 1.1 m/s vs 6.5 ± 0.6 m/s, P = 0.04). CONCLUSIONS Subclinical vascular disease is not greater in CHC subjects compared with controls. However, among CHC subjects, genotype 1 infection is associated with greater endothelial dysfunction and increased carotid-intima medial thickness compared with non-genotype 1 infection. Successful viral eradication may improve insulin resistance and arterial stiffness.
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Affiliation(s)
- P Pateria
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital
| | - G P Jeffrey
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
| | - G MacQuillan
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
| | - D Speers
- PathWest Laboratory Medicine WA, Queen Elizabeth II Medical Centre
| | - H Ching
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
| | - M A Chinnaratha
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital
| | - G F Watts
- School of Medicine and Pharmacology, University of Western Australia.,Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia
| | - L A Adams
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
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18
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Afify M, Hamza AH, Alomari RA. Correlation Between Serum Cytokines, Interferons, and Liver Functions in Hepatitis C Virus Patients. J Interferon Cytokine Res 2016; 37:32-38. [PMID: 27726476 DOI: 10.1089/jir.2016.0044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
To provide fundamental insights into the mechanism of Hepatitis C virus (HCV), we conduct the present study to improve further understanding of the interaction between HCV and cytokines. Two hundred one patients were enrolled in this study. Seventy-eight patients matching the study group in terms of age and gender with negative serology for hepatitis viruses, HIV virus, and with liver enzyme levels within normal range were selected as the control group. Patients were diagnosed with positive hepatitis C by detection of positive HCV antibodies in serum. Interferon-gamma (IFN-γ) and interleukin (IL)-10 were measured in positive and negative patients. Also liver functions (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma glutamyl transferase [GGT], alkaline phosphatase [ALP], urea, total protein, albumin, total and direct bilirubin) were also measured. Our results indicated significant elevation in IL-10 and IFN-γ in positive hepatitis C patients. These elevations were accompanied by significant elevation in liver function biomarkers with significant regression in albumin and total protein content. Furthermore, IFN-γ significantly increased immune response of cellular immunity. IL-10 significantly decreased immune response of cellular immunity by inhibiting IFN-γ and other production of Th. Liver function levels can be used as a marker for HCV. The findings from our study recommend IL-10 pathway in HCV infection and use IFNs to increase immune response for viral hepatitis.
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Affiliation(s)
- Mona Afify
- 1 Microbiology Section, Biology Department, King Abdulaziz University , Jeddah, Kingdom of Saudi Arabia.,2 Faculty of Medicine, Medical Microbiology and Immunology Department, Zagazig University , Cairo, Egypt
| | - Amal H Hamza
- 3 Biochemistry Department, King Abdulaziz University , Jeddah, Kingdom of Saudi Arabia.,4 Faculty of Women, Biochemistry and Nutrition Department, Ain Shams University , Cairo, Egypt
| | - Reem A Alomari
- 1 Microbiology Section, Biology Department, King Abdulaziz University , Jeddah, Kingdom of Saudi Arabia
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19
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Protective Effects of Dracocephalum heterophyllum in ConA-Induced Acute Hepatitis. Mediators Inflamm 2016; 2016:2684321. [PMID: 27524863 PMCID: PMC4976189 DOI: 10.1155/2016/2684321] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 05/29/2016] [Indexed: 01/26/2023] Open
Abstract
Dracocephalum heterophyllum (DH) is a Chinese herbal medicine used in treating hepatitis. However, the protective effects and pharmacological mechanisms of DH in hepatitis are unknown. In this study, we found that pretreatment with DH extract significantly ameliorated liver injury and suppressed the production of inflammatory cytokines, including tumor necrosis factor (TNF-α) and interferon-γ (IFN-γ) in Concanavalin A- (ConA-) induced hepatitis (CIH). DH recruited more CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs) to the liver and suppressed infiltration of macrophages (Kupffer cells) in the liver. The present work explores DH as an effective hepatoprotective medicine to inhibit inflammation and liver injury caused by hepatitis.
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20
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Grandi T, Silva CMDD, Amaral KM, Picon PD, Costi C, Fré NND, Fiegenbaum M, Gregianini TS, Niel C, Rossetti MLR. Tumour necrosis factor -308 and -238 promoter polymorphisms are predictors of a null virological response in the treatment of Brazilian hepatitis C patients. Mem Inst Oswaldo Cruz 2016; 109:345-51. [PMID: 24789557 PMCID: PMC4131788 DOI: 10.1590/0074-0276130372] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 12/17/2013] [Indexed: 02/07/2023] Open
Abstract
Certain host single nucleotide polymorphisms (SNPs) affect the likelihood of a
sustained virological response (SVR) to treatment in subjects infected with hepatitis
C virus (HCV). SNPs in the promoters of interleukin (IL)-10 (-1082 A/G, rs1800896),
myxovirus resistance protein 1 (-123 C/A, rs17000900 and -88 G/T, rs2071430) and
tumour necrosis factor (TNF) (-308 G/A, rs1800629 and -238 G/A, rs361525) genes and
the outcome of PEGylated α-interferon plus ribavirin therapy were investigated. This
analysis was performed in 114 Brazilian, HCV genotype 1-infected patients who had a
SVR and in 85 non-responders and 64 relapsers. A significantly increased risk of
having a null virological response was observed in patients carrying at least one A
allele at positions -308 [odds ratios (OR) = 2.58, 95% confidence intervals (CI) =
1.44-4.63, p = 0.001] or -238 (OR = 7.33, 95% CI = 3.59-14.93, p < 0.001) in the
TNF promoter. The risk of relapsing was also elevated (-308: OR = 2.87, 95% CI =
1.51-5.44, p = 0.001; -238: OR = 4.20, 95% CI = 1.93-9.10, p < 0.001). Multiple
logistic regression of TNF diplotypes showed that patients with at least two copies
of the A allele had an even higher risk of having a null virological response (OR =
16.43, 95% CI = 5.70-47.34, p < 0.001) or relapsing (OR = 6.71, 95% CI =
2.18-20.66, p = 0.001). No statistically significant association was found between
the other SNPs under study and anti-HCV therapy response.
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Affiliation(s)
- Tarciana Grandi
- Centro de Desenvolvimento Científico e Tecnológico, Fundação Estadual de Produção e Pesquisa em Saúde, Porto Alegre, RS, Brasil
| | | | - Karine Medeiros Amaral
- Centro de Aplicação e Monitorização de Medicamentos Injetáveis, Porto Alegre, RS, Brasil
| | - Paulo Dornelles Picon
- Centro de Aplicação e Monitorização de Medicamentos Injetáveis, Porto Alegre, RS, Brasil
| | - Cintia Costi
- Centro de Desenvolvimento Científico e Tecnológico, Fundação Estadual de Produção e Pesquisa em Saúde, Porto Alegre, RS, Brasil
| | - Nicole Nascimento da Fré
- Centro de Desenvolvimento Científico e Tecnológico, Fundação Estadual de Produção e Pesquisa em Saúde, Porto Alegre, RS, Brasil
| | | | - Tatiana Schäffer Gregianini
- Laboratório de Vírus Respiratórios, Fundação Estadual de Produção e Pesquisa em Saúde, Porto Alegre, RS, Brasil
| | - Christian Niel
- Laboratório de Virologia Molecular, Instituto Oswaldo Cruz-Fiocruz, Rio de Janeiro, RJ, Brasil
| | - Maria Lucia Rosa Rossetti
- Centro de Desenvolvimento Científico e Tecnológico, Fundação Estadual de Produção e Pesquisa em Saúde, Porto Alegre, RS, Brasil
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Attallah AM, El-Far M, Zahran F, Shiha GE, Farid K, Omran MM, Abdelrazek MA, Attallah AA, El-Beh AA, El-Hosiny RM, El-Waseef AM. Interferon-gamma is associated with hepatic dysfunction in fibrosis, cirrhosis, and hepatocellular carcinoma. J Immunoassay Immunochem 2016; 37:597-610. [PMID: 27093468 DOI: 10.1080/15321819.2016.1179646] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The relation between interferon-gamma (IFN-γ) levels and the severity of liver diseases through fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) has not been fully clarified. Thus, we aimed to characterize IFN-γ levels in liver-diseased patients. IFN-γ levels were determined by Western-blot and ELISA in sera from 30 healthy individuals, 53 patients with non-significant fibrosis (F0-F1), 47 with moderate/severe fibrosis (F2-F3), 44 cirrhotic patients (F4), and 50 with HCC. Enhanced levels of IFN-γ were associated with the progression of liver disease. The differences were statistically significant (P < 0.0001) when patients with F2-F3, F4, or HCC were compared with F0-F1 or healthy controls. The increase in IFN-γ was associated with HCC (OR = 0.98, 95% CI 0.97-0.99, P = 0.002). There was no statistically significant association between IFN-γ levels and HCV-RNA (IU/ml) (r = 0.1, P = 0.43) or HCV-NS4 (µg/mL) (r = 0.1, P = 0.17). There was significant (P < 0.0001) association between IFN-γ levels and the fibrosis stages and activity, albumin, platelet count, total bilirubin, and international normalized ratio (INR). In conclusion, elevated concentrations of IFN-γ represent a characteristic feature of liver disease severity regardless of underlying disease. Significant correlations with indices of hepatic dysfunction suggest that enhanced IFN-γ levels represent a consequence of liver dysfunction rather than of inflammatory disease.
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Affiliation(s)
- Abdelfattah M Attallah
- a Research and Development Department , Biotechnology Research Center , New Damietta , Egypt
| | - Mohamed El-Far
- b Chemistry Department, Faculty of Science , Mansoura University , Mansoura , Egypt
| | - Faten Zahran
- c Chemistry Department, Faculty of Science , Zagazig University , Zagazig , Egypt
| | - Gamal E Shiha
- d Department of Internal Medicine, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - Khaled Farid
- e Tropical Medicine Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - Mohamed M Omran
- f Chemistry Department, Faculty of Science , Helwan University , Cairo , Egypt
| | - Mohamed A Abdelrazek
- a Research and Development Department , Biotechnology Research Center , New Damietta , Egypt
| | - Ahmed A Attallah
- a Research and Development Department , Biotechnology Research Center , New Damietta , Egypt
| | - Amira A El-Beh
- a Research and Development Department , Biotechnology Research Center , New Damietta , Egypt
| | - Radwa M El-Hosiny
- a Research and Development Department , Biotechnology Research Center , New Damietta , Egypt
| | - Ahmed M El-Waseef
- b Chemistry Department, Faculty of Science , Mansoura University , Mansoura , Egypt
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22
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Rauff B, Douglas MW. Role of fibrogenic and inflammatory cytokines in HCV-induced fibrosis. Future Virol 2015. [DOI: 10.2217/fvl.15.102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
HCV is one of the main causative agents of liver fibrosis and hepatocellular carcinoma. Liver inflammation resulting from HCV infection triggers fibrosis. In HCV-related fibrosis, differentiated hepatic stellate cells (HSCs) known as myofibroblasts participate in the fibrogenic and inflammatory response. TGF-β1 and CTGF, released from these HSCs, have been implicated as master cytokines mediating HCV induced hepatic fibrosis. PDGF is another potent mitogen, which facilitates the progression of liver fibrosis by enhancing the proliferation and migration of HSCs. In addition to these major cytokines, the release of TNF-α, IL-6, IL-1b and IL-10 by immune cells also promotes the effect of HCV induced fibrosis. Targeting these cytokines may offer the potential for treatments to prevent or cure fibrosis.
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Affiliation(s)
- Bisma Rauff
- Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW, Australia
| | - Mark W Douglas
- Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW, Australia
- Centre for Infectious Diseases & Microbiology, Marie Bashir Institute for Infectious Diseases & Biosecurity, University of Sydney at Westmead Hospital, NSW, Australia
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23
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Noritake H, Kobayashi Y, Ooba Y, Matsunaga E, Ohta K, Shimoyama S, Yamazaki S, Chida T, Kawata K, Sakaguchi T, Suda T. Successful Interferon Therapy Reverses Enhanced Hepatic Progenitor Cell Activation in Patients with Chronic Hepatitis C. J Interferon Cytokine Res 2015; 35:956-62. [PMID: 26308703 DOI: 10.1089/jir.2014.0197] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The enhanced accumulation of hepatic progenitor cells (HPCs) is related to the risk of progression to hepatocellular carcinoma (HCC). Interferon (IFN) treatment reduces HCC risk in patients with chronic hepatitis C virus (HCV) infection. However, the underlying mechanisms remain unclear. The aim of this study was to examine the effects of IFN treatment on HPC activation in HCV patients. Immunohistochemical detection and computer-assisted quantitative image analyses of cytokeratin 7 (CK7) were performed to evaluate HPC activation in paired pre- and post-treatment liver biopsies from 18 HCV patients with sustained virological response (SVR) to IFN-based therapy and from 23 patients without SVR, as well as normal liver tissues obtained from surgical resection specimens of 10 patients. Pretreatment HCV livers showed increased CK7 immunoreactivity, compared with normal livers (HCV: median, 1.38%; normal: median, 0.69%, P=0.006). IFN treatment reduced hepatic CK7 immunoreactivity (median, 1.57% pre-IFN vs. 0.69% post-IFN, P=0.006) in SVR patients, but not in non-SVR patients. The development of HCC following IFN treatment was encountered in 3 non-SVR patients who showed high post-IFN treatment CK7 immunoreactivity (>4%). Successful IFN therapy can reverse enhanced HPC activation in HCV patients, which may contribute to the reduced risk of HCC development in these patients.
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Affiliation(s)
- Hidenao Noritake
- 1 Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine , Hamamatsu, Japan
| | - Yoshimasa Kobayashi
- 1 Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine , Hamamatsu, Japan
| | - Yukimasa Ooba
- 1 Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine , Hamamatsu, Japan
| | - Erika Matsunaga
- 1 Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine , Hamamatsu, Japan
| | - Kazuyoshi Ohta
- 1 Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine , Hamamatsu, Japan
| | - Shin Shimoyama
- 1 Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine , Hamamatsu, Japan
| | - Satoru Yamazaki
- 1 Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine , Hamamatsu, Japan
| | - Takeshi Chida
- 1 Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine , Hamamatsu, Japan
| | - Kazuhito Kawata
- 1 Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine , Hamamatsu, Japan
| | - Takanori Sakaguchi
- 2 Department of Surgery, Hamamatsu University School of Medicine , Hamamatsu, Japan
| | - Takafumi Suda
- 3 Respiratology Division, Department of Internal Medicine, Hamamatsu University School of Medicine , Hamamatsu, Japan
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El-Araby HA, Ehsan NA, Konsowa HA, Abd-Elaati BM, Sira AM. Hepatic progenitor cells in children with chronic hepatitis C: correlation with histopathology, viremia, and treatment response. Eur J Gastroenterol Hepatol 2015; 27:561-569. [PMID: 25822865 DOI: 10.1097/meg.0000000000000329] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Hepatic progenitor cells (HPCs) are bipotential stem cells that can differentiate towards the hepatocytic and cholangiocytic lineages. Many studies have investigated HPCs in adults with hepatitis C virus infection; however, none has been carried out in the pediatric population. Therefore, this work aimed to investigate HPCs expansion in children with chronic hepatitis C (CHC) and its correlation with histopathology, viremia, and treatment response. PATIENTS AND METHODS Eighty children with CHC, 73 of whom received interferon-based therapy, were recruited. Sections of their liver biopsies were prepared for immunostaining of HPCs using cytokeratin-7 antibody. RESULTS HPCs were expanded in most children (81.3%) with CHC. Expansion occurred in two forms: intraparenchymal isolated hepatic progenitor cell form and periportal ductular reaction form. There was a significant increase in HPCs expansion in higher stages of fibrosis (50, 81.8, and 100% in no, mild, and moderate fibrosis, respectively, with P=0.029). Also, HPCs expansion increased with increased grade of necroinflammatory activity (0, 77.8, 81.8, and 100%, in no, minimal, mild, and moderate activity, respectively), although this was statistically insignificant. Moreover, a significant positive correlation was found between the isolated hepatic progenitor cell number and ductular reaction grade (r=0.755, P<0.0001), and both were significantly correlated with the level of viremia and the grade of necroinflammatory activity. Finally, HPCs expansion was not related to the treatment response. CONCLUSION The relationship of HPCs with both the severity of hepatitis and the stage of fibrosis may be because of a role of HPCs in their pathogenesis.
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Affiliation(s)
- Hanaa A El-Araby
- Departments of aPediatric Hepatology bPathology, National Liver Institute, Menofiya University, Menofiya, Egypt
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Plompen EPC, Hansen BE, Schouten JNL, Darwish Murad S, Loth DW, Brouwer WP, Isaacs A, Taimr P, Hofman A, van Duijn CM, Uitterlinden AG, Stricker BHC, Leebeek FWG, Janssen HLA. Interferon gamma receptor 2 gene variants are associated with liver fibrosis in the general population: the Rotterdam Study. Gut 2015; 64:692-4. [PMID: 25301852 DOI: 10.1136/gutjnl-2014-308398] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- Elisabeth P C Plompen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands Department of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | | | - Sarwa Darwish Murad
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Daan W Loth
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Willem Pieter Brouwer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Aaron Isaacs
- Department of Genetic Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Pavel Taimr
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Albert Hofman
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Cornelia M van Duijn
- Department of Genetic Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - André G Uitterlinden
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Bruno H C Stricker
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Frank W G Leebeek
- Department of Hematology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Ontario, Canada
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26
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Guo PF, Jin J, Sun X. Influence of IL10 gene polymorphisms on the severity of liver fibrosis and susceptibility to liver cirrhosis in HBV/HCV-infected patients. INFECTION GENETICS AND EVOLUTION 2014; 30:89-95. [PMID: 25514046 DOI: 10.1016/j.meegid.2014.12.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 12/04/2014] [Accepted: 12/08/2014] [Indexed: 01/17/2023]
Abstract
BACKGROUND Previous studies about the association of the interleukin-10 (IL-10) polymorphisms with the progression of liver fibrosis or cirrhosis susceptibility in chronic hepatitis B/C (CHB/C) disease were inconsistent. The aim of this meta-analysis was to derive a more precise estimation of the association. METHODS We searched Medline, PubMed, EMBASE and Web of Science electronic databases using the following key words: liver fibrosis/cirrhosis, IL10, and polymorphism. Statistical analyses were performed by STATA11.0 software, with odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS 12 independent studies in relation to IL10-1082A/G, -819C/T and -592C/A polymorphisms were included in our study, which consisted of 197 moderate/severe liver fibrosis cases and 426 mild fibrosis controls as well as 536 liver cirrhosis cases and 881 non-cirrhosis controls. The results indicated that a significantly decreased risk of moderate/severe fibrosis was associated with the GCC haplotype (IL10-1082G, -819C and -592C) in the overall CHB/C patients (OR: 0.547, 95% CI: 0.317-0.946, P=0.031). We did not detect any significant association between these polymorphisms and liver cirrhosis susceptibility in the total population or a subgroup of Asians. However, subgroup analyses by different aetiologies showed that the -819T heterozygotes (TC) were associated with a significantly increased risk of HCV-related liver cirrhosis in the Japanese population (OR: 1.254, 95% CI: 1.033-1.522, P=0.022). CONCLUSIONS The putative high IL-10 production haplotype GCC is more likely to be associated with less severe liver fibrosis in CHB/C patients. Additionally, the IL10-819T allele may be a susceptible factor for HCV-related liver cirrhosis in the Japanese population.
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Affiliation(s)
- Peng-Fei Guo
- Department of Mathematics, South China University of Technology, Guangzhou, China.
| | - Juan Jin
- School of Laboratory Medicine, Xinxiang Medical University, 601 Jinsui Road, Hongqi District, Xinxiang, Henan 453003, China
| | - Xiangru Sun
- Institute of Reproductive Medicine, Panyu Hexian Memorial Hospital of Guangzhou, 2 East of Qinghe Road, Panyu District, Guangzhou 511400, China
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27
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Abstract
INTRODUCTION Assessing the formation and regression of fibrosis in chronic liver disease (CLD) is important. Current methods of assessment employed in clinical practice are inadequate. We present a review of the utility of non-invasive biomarkers of liver fibrosis. SOURCES OF DATA Published material on MEDLINE. AREAS OF AGREEMENT Liver biopsy is an imperfect 'gold standard'. Biomarkers are excellent at detecting significant fibrosis across different aetiologies of CLD. There is growing evidence that they also predict clinical outcomes. AREAS OF CONTROVERSY Non-invasive biomarkers can be used in clinical practice to screen for significant fibrosis, but the utility of liver biopsy is retained in answering specific questions. Biomarkers cannot be used robustly in clinical trials as doubts remain over their ability to detect small changes in fibrosis, inflammation and what influences them. AREAS TIMELY FOR DEVELOPING RESEARCH Community screening and algorithms are being developed with biomarkers to more effectively direct resources. Novel imaging techniques have huge potential advantages, particularly in secondary care for risk stratification.
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Affiliation(s)
- Robert Scott
- National Institute for Health Research Nottingham Digestive Diseases Biomedical Research Unit (NDDBRU), Nottingham University Hospitals NHS Trust and University of Nottingham, E Floor, West Block QMC, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Indra Neil Guha
- National Institute for Health Research Nottingham Digestive Diseases Biomedical Research Unit (NDDBRU), Nottingham University Hospitals NHS Trust and University of Nottingham, E Floor, West Block QMC, Queen's Medical Centre, Nottingham NG7 2UH, UK
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28
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Talaat RM, Dondeti MF, El-Shenawy SZ, Khamiss OA. Association between IL-10 gene promoter polymorphism and hepatitis B viral infection in an Egyptian population. Biochem Genet 2014; 52:387-402. [PMID: 24838671 DOI: 10.1007/s10528-014-9655-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2013] [Accepted: 12/22/2013] [Indexed: 12/17/2022]
Abstract
Cytokines play critical roles in the pathogenesis of hepatitis B virus infection (HBV). This work was designed to study the effect of IL-10 gene polymorphisms (-1082G/A and -819C/T) on susceptibility of Egyptians to HBV. Genotyping was performed using single-stranded polymorphism-polymerase chain reaction in 118 Egyptian hepatitis B patients and 119 healthy controls, and IL-10 serum levels were measured using ELISA. The frequency of IL-10 -1082G/G was significantly higher in HBV patients than in healthy controls, and G/A and A/A were not significantly different between groups. The distribution of IL-10 -819 genotypes was not significantly different between the HBV and healthy control groups. Although AT was significantly different between controls and patients, the distribution of the other haplotypes was not. IL-10 levels were significantly lower among hepatitis B patients. Our data stress the importance of IL-10 gene polymorphism in HBV infection. Depending on our preliminary work, IL-10 -1082G/G may act as a host genetic factor in the susceptibility to HBV infection in Egyptians.
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Affiliation(s)
- Roba M Talaat
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Sadat City, Egypt,
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29
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Tarragô AM, da Costa AG, Pimentel JPD, Gomes STM, Freitas FB, Lalwani P, de Araújo ARS, Victória FDS, Victória MB, Vallinoto ACR, Sadahiro A, Teixeira-Carvalho A, Martins-Filho OA, Malheiro A. Combined impact of hepatitis C virus genotype 1 and interleukin-6 and tumor necrosis factor-α polymorphisms on serum levels of pro-inflammatory cytokines in Brazilian HCV-infected patients. Hum Immunol 2014; 75:1075-83. [PMID: 25193024 DOI: 10.1016/j.humimm.2014.08.198] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 08/18/2014] [Accepted: 08/18/2014] [Indexed: 12/31/2022]
Abstract
We investigated the association between hepatitis C virus (HCV) genotypes and host cytokine gene polymorphisms and serum cytokine levels in patients with chronic hepatitis C. Serum IL-6, TNF-α, IL-2, IFN-γ, IL-4, IL-10, and IL-17A levels were measured in 67 HCV patients (68.2% genotype 1 [G1]) and 47 healthy controls. The HCV patients had higher IL-6, IL-2, IFN-γ, IL-10, and IL-17A levels than the controls. HCV G1 patients had higher IL-2 and IFN-γ levels than G2 patients. The -174IL6G>C, -308TNFαG>A, and -1082IL10A>G variants were similarly distributed in both groups. However, HCV patients with the -174IL6GC variant had higher IL-2 and IFN-γ levels than patients with the GG and CC variants. Additionally, HCV patients with the -308TNFαGG genotype had higher IL-17A levels than patients with the AG genotype, whereas patients with the -1082IL10GG variant had higher IL-6 levels than patients with the AA and AG variants. A significant proportion of HCV patients had high levels of both IL-2 and IFN-γ. The subgroup of HCV patients with the G1/IL6CG/TNFαGG association displayed the highest proportions of high producers of IL-2 and IFN-γ whereas the subgroup with the G1/TNFαGG profile showed high proportions of high producers of IL-6 and IL-17A. HCV patients with other HCV/cytokine genotype associations showed no particular cytokine profile. Our results suggest that HCV genotype G1 and IL-6 and TNF-α polymorphisms have a clinically relevant influence on serum pro-inflammatory cytokine profile (IL-2 and IFN-γ) in HCV patients.
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Affiliation(s)
- Andréa Monteiro Tarragô
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, 3000, Rodrigo Otávio Av., Manaus, AM, Brazil; Fundação de Hematologia e Hemoterapia do Amazonas - HEMOAM, 3497 Constantino Nery Av., Manaus, AM, Brazil
| | - Allyson Guimarães da Costa
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, 3000, Rodrigo Otávio Av., Manaus, AM, Brazil; Fundação de Hematologia e Hemoterapia do Amazonas - HEMOAM, 3497 Constantino Nery Av., Manaus, AM, Brazil; Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, 25 Pedro Teixeira Av., Manaus, AM, Brazil
| | - João Paulo Diniz Pimentel
- Fundação de Hematologia e Hemoterapia do Amazonas - HEMOAM, 3497 Constantino Nery Av., Manaus, AM, Brazil; Instituto Leônidas e Maria Deane - FIOCRUZ-Amazônia, 476 Terezina St., Manaus, AM, Brazil
| | | | | | - Pritesh Lalwani
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, 3000, Rodrigo Otávio Av., Manaus, AM, Brazil
| | - Ana Ruth S de Araújo
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, 25 Pedro Teixeira Av., Manaus, AM, Brazil
| | - Flamir da Silva Victória
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, 25 Pedro Teixeira Av., Manaus, AM, Brazil
| | - Marilú Barbieri Victória
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, 25 Pedro Teixeira Av., Manaus, AM, Brazil
| | | | - Aya Sadahiro
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, 3000, Rodrigo Otávio Av., Manaus, AM, Brazil; Instituto Nacional de Pesquisas da Amazônia - INPA, 2936 André Araújo Av., Manaus, AM, Brazil
| | - Andréa Teixeira-Carvalho
- Centro de Pesquisas René Rachou - FIOCRUZ-Minas, 1715 Augusto de Lima Av., Belo Horizonte, MG, Brazil
| | | | - Adriana Malheiro
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, 3000, Rodrigo Otávio Av., Manaus, AM, Brazil; Fundação de Hematologia e Hemoterapia do Amazonas - HEMOAM, 3497 Constantino Nery Av., Manaus, AM, Brazil.
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30
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Hetta HF, Mehta MJ, Shata MTM. Gut immune response in the presence of hepatitis C virus infection. World J Immunol 2014; 4:52-62. [DOI: 10.5411/wji.v4.i2.52] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 05/22/2014] [Accepted: 06/20/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) is an important etiologic agent of hepatitis and a major cause of chronic liver infection that often leads to cirrhosis, fibrosis and hepatocellular carcinoma. Although, HCV is a hepatotropic virus, there is strong evidence that HCV could replicate extra-hepatic in the gastrointestinal tissue which could serve as a reservoir for HCV. The outcome of HCV infection depends mainly on the host innate and adaptive immune responses. Innate immunity against HCV includes mainly nuclear factor cells and activation of IFN-related genes. There is an immunologic link between the gut and the liver through a population of T-cells that are capable of homing to both the liver and gut via the portal circulation. However, little is known on the role of Gut immune response in HCV. In this review we discussed the immune regulation of Gut immune cells and its association with HCV pathogenesis, various outcomes of anti-HCV therapy, viral persistence and degree of liver inflammation. Additionally, we investigated the relationship between Gut immune responses to HCV and IL28B genotypes, which were identified as a strong predictor for HCV pathogenesis and treatment outcome after acute infection.
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Abstract
Persistent viral infection, such as HCV infection, is the result of the inability of the host immune system to mount a successful antiviral response, as well as the escape strategies devised by the virus. Although each individual component of the host immune system plays important roles in antiviral immunity, the interactive network of immune cells as a whole acts against the virus. The innate immune system forms the first line of host defense against viral infection, and thus, virus elimination or chronic HCV infection is linked to the direct outcome of the interactions between the various innate immune cells and HCV. By understanding how the distinct components of the innate immune system function both individually and collectively during HCV infection, potential therapeutic targets can be identified to overcome immune dysfunction and control chronic viral infection.
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Affiliation(s)
- Banishree Saha
- University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Gyongyi Szabo
- University of Massachusetts Medical School, Worcester, Massachusetts, USA
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32
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Rosendahl Huber S, van Beek J, de Jonge J, Luytjes W, van Baarle D. T cell responses to viral infections - opportunities for Peptide vaccination. Front Immunol 2014; 5:171. [PMID: 24795718 PMCID: PMC3997009 DOI: 10.3389/fimmu.2014.00171] [Citation(s) in RCA: 147] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 03/31/2014] [Indexed: 12/22/2022] Open
Abstract
An effective immune response against viral infections depends on the activation of cytotoxic T cells that can clear infection by killing virus-infected cells. Proper activation of these T cells depends on professional antigen-presenting cells, such as dendritic cells (DCs). In this review, we will discuss the potential of peptide-based vaccines for prevention and treatment of viral diseases. We will describe features of an effective response against both acute and chronic infections, such as an appropriate magnitude, breadth, and quality and discuss requirements for inducing such an effective antiviral immune response. We will address modifications that affect presentation of vaccine components by DCs, including choice of antigen, adjuvants, and formulation. Furthermore, we will describe differences in design between preventive and therapeutic peptide-based vaccines. The ultimate goal in the design of preventive vaccines is to develop a universal vaccine that cross-protects against multiple strains of the virus. For therapeutic vaccines, cross-protection is of less importance, but enhancing existing T cell responses is essential. Although peptide vaccination is successful in inducing responses in human papillomavirus (HPV) infected patients, there are still several challenges such as choosing the right target epitopes, choosing safe adjuvants that improve immunogenicity of these epitopes, and steering the immune response in the desired direction. We will conclude with an overview of the current status of peptide vaccination, hurdles to overcome, and prospects for the future.
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Affiliation(s)
- Sietske Rosendahl Huber
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Josine van Beek
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Jørgen de Jonge
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Willem Luytjes
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Debbie van Baarle
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
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Helal SF, Gomaa HE, Thabet EH, Younan MA, Helmy NA. Impact of IL-10 (-1082) promoter-single nucleotide polymorphism on the outcome of hepatitis C virus genotype 4 infection. CLINICAL MEDICINE INSIGHTS. GASTROENTEROLOGY 2014; 7:19-24. [PMID: 24833945 PMCID: PMC4019231 DOI: 10.4137/cgast.s13658] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Revised: 01/23/2014] [Accepted: 01/27/2014] [Indexed: 12/18/2022]
Abstract
UNLABELLED Immunoregulatory cytokines may influence the hepatitis C virus (HCV) infection outcome. This study aimed to determine the genotypic and allelic frequencies of the interleukin (IL)-10 (-1082) G/A polymorphism, and its association with chronicity or resolution of HCV genotype 4 infection in Egypt. The frequencies of different dimorphic polymorphisms based on single nucleotide substitution in chronic HCV patients (50) and resolved HCV patients (50) were: IL-10 (-1082) G/G 22 (44%) and 18 (36%), G/A 19 (38%) and 24 (48%), and A/A 9 (18%), and 8 (16%), respectively. In the sustained virologic response (SVR) (36) and spontaneously resolved subjects (14) groups, the frequencies were: IL-10 (-1082) G/G 11 (30.6%) and 7 (50%) G/A 18 (50%) and 6 (42.9%), A/A 7 (19.4%) and 1 (7.1%), respectively. An association between male gender and chronic hepatitis C outcome (P value 0.041) was found. However, no significant gender difference was found when we compared females versus males with elevated alanine transaminase (ALT) levels in the chronic HCV patient group (P value = 1). CONCLUSION No significant difference in the frequency of IL-10 single nucleotide polymorphism (SNP) at position 1082 was found between chronic and resolved HCV subjects.
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Affiliation(s)
- Soheir F Helal
- Virology and Clinical Pathology Department, Cairo University, Egypt
| | - Howayda E Gomaa
- Clinical and Chemical Pathology Department, National Research Centre, Cairo, Egypt
| | - Eman H Thabet
- Clinical and Chemical Pathology Department, National Research Centre, Cairo, Egypt
| | - Mariam A Younan
- Virology and Clinical Pathology Department, Cairo University, Egypt
| | - Neveen A Helmy
- Clinical and Chemical Pathology Department, National Research Centre, Cairo, Egypt
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Kularatne SAM, Imbulpitiya IVB, Abeysekera RA, Waduge RN, Rajapakse RPVJ, Weerakoon KGAD. Extensive haemorrhagic necrosis of liver is an unpredictable fatal complication in dengue infection: a postmortem study. BMC Infect Dis 2014; 14:141. [PMID: 24628767 PMCID: PMC4008311 DOI: 10.1186/1471-2334-14-141] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 03/10/2014] [Indexed: 12/31/2022] Open
Abstract
Background Dengue infection carries a potential risk of death despite stringent management of plasma leak and haemorrhage. It appears that the extent of liver dysfunction determines the outcome. Methods We present a postmortem study of five patients, died of dengue shock syndrome who had markedly elevated liver enzymes and irreparable circulatory failure. Results All were females with a median age of 46 years (range 20–50 years). All had positive NS1 and IgM. Clinically, one patient developed severe degree of hepatic encephalopathy whilst three patients developed uncontrollable bleeding manifestations. Dengue virus was detected in three liver specimens by reverse transcription PCR. Histology of the liver revealed massive necrosis with haemorrhages in these patients with evidence of micro and macrovesicular steatosis with significant periportal inflammatory infiltrate. No significant ischaemic changes or necrosis was observed in the other organs. Conclusions Severe haemorrhagic necrosis of the liver was the cause of death in these patients probably due to direct viral infection. Predilection for severe liver disease remains unknown. Therefore, it is prudent to think beyond plasma leak as the main pathology of dengue infection and attempts should be made to develop other treatment modalities to prevent and manage unforeseen fatal complications of dengue infection.
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Liu G, Bi Y, Wang R, Yang H, Zhang Y, Wang X, Liu H, Lu Y, Zhang Z, Chen W, Chu Y, Yang R. Targeting S1P1 receptor protects against murine immunological hepatic injury through myeloid-derived suppressor cells. THE JOURNAL OF IMMUNOLOGY 2014; 192:3068-79. [PMID: 24567529 DOI: 10.4049/jimmunol.1301193] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Although FTY720 may alter migration and homing of lymphocytes via sphingosine-1-phosphate (S1P) receptors, our recent studies indicated that FTY720 directly controls the differentiation of Th1 cells to regulatory T cells (Tregs) by targeting S1P1. However, the pharmacological function of FTY720 in immunological hepatic injury remains unknown. In this study, the role and regulatory signaling pathway of S1P receptor were investigated using a pharmacological approach in immune-mediated hepatic injury (IMH). In the context of IMH, FTY720 significantly ameliorated mortality and hepatic pathology. In FTY720-treated mice, recruited CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) mediate protection against IMH and are functional suppressive immune modulators that result in fewer IFN-γ-producing Th1 cells and more Foxp3(+) Tregs. In agreement, FTY720-treated MDSCs promote the reciprocal differentiation between Th1 cells and Tregs in vitro and in vivo. Mechanistically, FTY720 treatment induced inducible NO synthase expression and NO production in MDSCs. Pharmacologic inhibition of inducible NO synthase completely eliminates MDSC suppressive function and eradicates their inducible effects on T cell differentiation. Finally, the mTOR inhibitor, rapamycin, photocopies the effects of FTY720 on MDSCs, implicating mTOR as a downstream effector of S1P1 signaling. This study identifies MDSCs as an essential component that provides protection against IMH following FTY720 or rapamycin treatment, validating the S1P1-mTOR signaling axis as a potential therapeutic target in hepatic injury.
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Affiliation(s)
- Guangwei Liu
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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36
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Xu M, Xie F, Qian G, Jing Y, Zhang S, Gao L, Zheng T, Wu M, Yang J, Wei L. Peritumoral ductular reaction: a poor postoperative prognostic factor for hepatocellular carcinoma. BMC Cancer 2014; 14:65. [PMID: 24495509 PMCID: PMC3916808 DOI: 10.1186/1471-2407-14-65] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 02/03/2014] [Indexed: 12/17/2022] Open
Abstract
Background The role of ductular reaction (DR) in hepatocellular carcinoma (HCC) remains to be elucidated. Methods In this study, we tried to uncover possible effect by correlating peritumoral DR in a necroinflammatory microenvironment with postoperative prognosis in HCC. The expression of peritumoral DR/CK19 by immunohistochemistry, necroinflammation and fibrosis were assessed from 106 patients receiving curative resection for HCC. Prognostic values for these and other clinicopathologic factors were evaluated. Results Peritumoral DR significantly correlated with necroinflammation (r = 0.563, p = 3.4E-10), fibrosis (r = 0.435, p = 3.1E-06), AFP level (p = 0.010), HBsAg (p = 4.9E-4), BCLC stage (p = 0.003), TNM stage (p = 0.002), multiple nodules (p = 0.004), absence of tumor capsule (p = 0.027), severe microscopic vascular invasion (p = 0.031) and early recurrence (p = 0.010). Increased DR was significantly associated with decreased RFS/OS (p = 4.8E-04 and p = 2.6E-05, respectively) in univariate analysis and were identified as an independent prognostic factor (HR = 2.380, 95% CI = 1.250-4.534, p = 0.008 for RFS; HR = 4.294, 95% CI = 2.255-8.177, p = 9.3E-6 for OS) in multivariate analysis. Conclusions These results suggested that peritumoral DR in a necroinflammatory microenvironment was a poor prognostic factor for HCC after resection.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jiamei Yang
- Tumor Immunology & Gene Therapy Center, Eastern Hepatobiliary Hospital, The Second Military Medical University, Changhai Road, Shanghai 200438, China.
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Mousa N, Eldars W, Eldegla H, Fouda O, Gad Y, Abousamra N, Elmasry E, Arafa M. Cytokine profiles and hepatic injury in occult hepatitis C versus chronic hepatitis C virus infection. Int J Immunopathol Pharmacol 2014; 27:87-96. [PMID: 24674682 DOI: 10.1177/039463201402700111] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/16/2024] Open
Abstract
Occult hepatitis C virus (HCV) infection is a new entity that should be considered when diagnosing patients with abnormal liver functions of unknown origin. This work was carried out to evaluate T-helper 1/T-helper 2 (Th1/Th2) cytokine profiles in patients with occult HCV infection versus chronic hepatitis C (CHC) infection, also to investigate any association between theses cytokines and liver histological features in both groups. Serum levels of Th1 cytokines (IL-2, IFN-gamma) and Th2 (IL-4 and IL-10) were measured in 35 patients with occult HCV infection compared to 50 patients with chronic hepatitis C infection and 30 healthy controls. We have found that Th1 cytokines were significantly increased in patients with CHC infection than in both occult HCV infection and control groups (p less than 0.001). On the other hand, serum IL-4 levels were higher in occult HCV infection than in CHC and control groups (p less than 0.001). Furthermore, serum IL-10 levels were higher in both patient groups vs control group (pless than 0.001), with no significant difference between CHC and occult HCV groups. Finally, only serum IL-10 levels were significantly higher among patients with high activity (A2-A3) than those with low activity (A0-A1) in both CHC and occult HCV groups (p=0.038, p=0.025, respectively). Patients with occult HCV infection exhibited a distinct immunoregulatory cytokine pattern that is shifted towards the Th2 arm.
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Affiliation(s)
- N Mousa
- Department of Tropical Medicine, Mansoura University, Egypt
| | - W Eldars
- Department of Medical Microbiology and Immunology, Mansoura University, Egypt
| | - H Eldegla
- Department of Medical Microbiology and Immunology, Mansoura University, Egypt
| | - O Fouda
- Department of Internal Medicine, Mansoura University, Egypt
| | - Y Gad
- Department of Internal Medicine, Mansoura University, Egypt
| | - N Abousamra
- Department of Clinical Pathology, Mansoura University, Egypt
| | - E Elmasry
- Department of Clinical Pathology, Mansoura University, Egypt
| | - M Arafa
- Department of Pathology, Mansoura University, Egypt
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Fuster D, Tsui JI, Cheng DM, Quinn EK, Armah KA, Nunes D, Freiberg MS, Samet JH. Interleukin-6 is associated with noninvasive markers of liver fibrosis in HIV-infected patients with alcohol problems. AIDS Res Hum Retroviruses 2013; 29:1110-6. [PMID: 23601055 DOI: 10.1089/aid.2012.0348] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Both HIV and hepatitis C virus (HCV) cause chronic inflammation and alterations in serum inflammatory cytokines. The impact of inflammatory cytokines on liver fibrosis is not well understood. We studied the association between interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α and liver fibrosis in HIV-infected patients with current or past alcohol problems (CAGE ≥2 or physician investigator diagnosis). Liver fibrosis was estimated with FIB-4 (FIB-4 <1.45 defined the absence of liver fibrosis and FIB-4 >3.25 defined advanced fibrosis). Logistic regression was used to assess the association between cytokines and fibrosis, adjusting for age, sex, CD4, HIV RNA, current antiretroviral therapy, body mass index, and HCV. Secondary analyses explored whether the association between HCV and liver fibrosis was mediated by these cytokines. Participants (n=308) were all HIV-infected; 73% were male with a mean age of 42 years; half had detectable HCV-RNA, 60.7% had an absence of liver fibrosis, and 10.1% had advanced fibrosis. In models that adjusted for each cytokine separately, higher levels of IL-6 were significantly associated with an absence of fibrosis [adjusted OR (95% CI): 0.43 (0.19, 0.98), p=0.05] and were borderline significant for advanced fibrosis [adjusted OR (95% CI): 8.16 (0.96, 69.54), p=0.055]. In the final model, only higher levels of IL-6 remained significantly associated with advanced liver fibrosis [adjusted OR (95% CI): 11.78 (1.17, 118.19), p=0.036]. Adjustment for inflammatory cytokines attenuated the adjusted OR for the association between HCV and fibrosis in the case of IL-6 [for the absence of fibrosis from 0.32 (0.17, 0.57) p<0.01 to 0.47 (0.23, 0.96) p=0.04; and for advanced fibrosis from 7.22 (2.01, 25.96) p<0.01 to 6.62 (1.20, 36.62) p=0.03], suggesting IL-6 may be a partial mediator of the association between HCV and liver fibrosis. IL-6 was strongly and significantly associated with liver fibrosis in a cohort of HIV-infected patients with alcohol problems. IL-6 may be a useful predictive marker for liver fibrosis for HIV-infected patients.
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Affiliation(s)
- Daniel Fuster
- Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
| | - Judith I. Tsui
- Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
| | - Debbie M. Cheng
- Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
| | - Emily K. Quinn
- Data Coordinating Center, Boston University School of Public Health, Boston, Massachusetts
| | - Kaku A. Armah
- Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - David Nunes
- Section of Gastroenterology, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
| | - Matthew S. Freiberg
- Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jeffrey H. Samet
- Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
- Department of Community Health Sciences, Boston University School of Public Health, Boston, Massachusetts
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Babudieri S, Soddu A, Nieddu P, Tanca A, Madeddu G, Addis M, Pagnozzi D, Cossu-Rocca P, Massarelli G, Dore M, Uzzau S, Mura M. Proteomic characterization of hepatitis C eradication: Enzyme switch in the healing liver. J Clin Virol 2013; 57:274-8. [DOI: 10.1016/j.jcv.2013.03.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 02/23/2013] [Accepted: 03/02/2013] [Indexed: 12/13/2022]
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40
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Aroucha D, do Carmo R, Moura P, Silva J, Vasconcelos L, Cavalcanti M, Muniz M, Aroucha M, Siqueira E, Cahú G, Pereira L, Coêlho M. High tumor necrosis factor-α/interleukin-10 ratio is associated with hepatocellular carcinoma in patients with chronic hepatitis C. Cytokine 2013; 62:421-5. [DOI: 10.1016/j.cyto.2013.03.024] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Revised: 03/23/2013] [Accepted: 03/23/2013] [Indexed: 12/15/2022]
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Hepatitis C virus infection induces inflammatory cytokines and chemokines mediated by the cross talk between hepatocytes and stellate cells. J Virol 2013; 87:8169-78. [PMID: 23678168 DOI: 10.1128/jvi.00974-13] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Inflammatory cytokines and chemokines play important roles in inflammation during viral infection. Hepatitis C virus (HCV) is a hepatotropic RNA virus that is closely associated with chronic liver inflammation, fibrosis, and hepatocellular carcinoma. During the progression of HCV-related diseases, hepatic stellate cells (HSCs) contribute to the inflammatory response triggered by HCV infection. However, the underlying molecular mechanisms that mediate HSC-induced chronic inflammation during HCV infection are not fully understood. By coculturing HSCs with HCV-infected hepatocytes in vitro, we found that HSCs stimulated HCV-infected hepatocytes, leading to the expression of proinflammatory cytokines and chemokines such as interleukin-6 (IL-6), IL-8, macrophage inflammatory protein 1α (MIP-1α), and MIP-1β. Moreover, we found that this effect was mediated by IL-1α, which was secreted by HSCs. HCV infection enhanced production of CCAAT/enhancer binding protein (C/EBP) β mRNA, and HSC-dependent IL-1α production contributed to the stimulation of C/EBPβ target cytokines and chemokines in HCV-infected hepatocytes. Consistent with this result, knockdown of mRNA for C/EBPβ in HCV-infected hepatocytes resulted in decreased production of cytokines and chemokines after the addition of HSC conditioned medium. Induction of cytokines and chemokines in hepatocytes by the HSC conditioned medium required a yet to be identified postentry event during productive HCV infection. The cross talk between HSCs and HCV-infected hepatocytes is a key feature of inflammation-mediated, HCV-related diseases.
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42
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Lang PA, Xu HC, Grusdat M, McIlwain DR, Pandyra AA, Harris IS, Shaabani N, Honke N, Maney SK, Lang E, Pozdeev VI, Recher M, Odermatt B, Brenner D, Häussinger D, Ohashi PS, Hengartner H, Zinkernagel RM, Mak TW, Lang KS. Reactive oxygen species delay control of lymphocytic choriomeningitis virus. Cell Death Differ 2013; 20:649-58. [PMID: 23328631 PMCID: PMC3595491 DOI: 10.1038/cdd.2012.167] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Cluster of differentiation (CD)8(+) T cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T-cell-mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus-infected liver and spleen tissues that were triggered by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8(+) T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T-cell function was elevated in p47phox-deficient (Ncf1(-/-)) mice. In the absence of p47phox, enhanced T-cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage.
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Affiliation(s)
- P A Lang
- Institute of Experimental Immunology, University Hospital of Zurich, Schmelzbergstrasse 12, Zurich 8091, Switzerland
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43
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Selmi C, Ceribelli A, Vierling JM. Suspected and unsuspected factors in the multifaceted immunopathology of viral hepatitis. Semin Immunopathol 2012; 35:1-5. [PMID: 23250654 DOI: 10.1007/s00281-012-0359-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 11/27/2012] [Indexed: 10/27/2022]
Affiliation(s)
- Carlo Selmi
- Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Milan, Italy
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Tosello-Trampont AC, Landes SG, Nguyen V, Novobrantseva TI, Hahn YS. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J Biol Chem 2012; 287:40161-72. [PMID: 23066023 DOI: 10.1074/jbc.m112.417014] [Citation(s) in RCA: 341] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The mechanisms triggering nonalcoholic steatohepatitis (NASH) remain poorly defined. RESULTS Kupffer cells are the first responding cells to hepatocyte injuries, leading to TNFα production, chemokine induction, and monocyte recruitment. The silencing of TNFα in myeloid cells reduces NASH progression. CONCLUSION Increase of TNFα-producing Kupffer cells is crucial for triggering NASH via monocyte recruitment. SIGNIFICANCE Myeloid cells-targeted silencing of TNFα might be a tenable therapeutic approach. Nonalcoholic steatohepatitis (NASH), characterized by lipid deposits within hepatocytes (steatosis), is associated with hepatic injury and inflammation and leads to the development of fibrosis, cirrhosis, and hepatocarcinoma. However, the pathogenic mechanism of NASH is not well understood. To determine the role of distinct innate myeloid subsets in the development of NASH, we examined the contribution of liver resident macrophages (i.e. Kupffer cells) and blood-derived monocytes in triggering liver inflammation and hepatic damage. Employing a murine model of NASH, we discovered a previously unappreciated role for TNFα and Kupffer cells in the initiation and progression of NASH. Sequential depletion of Kupffer cells reduced the incidence of liver injury, steatosis, and proinflammatory monocyte infiltration. Furthermore, our data show a differential contribution of Kupffer cells and blood monocytes during the development of NASH; Kupffer cells increased their production of TNFα, followed by infiltration of CD11b(int)Ly6C(hi) monocytes, 2 and 10 days, respectively, after starting the methionine/choline-deficient (MCD) diet. Importantly, targeted knockdown of TNFα expression in myeloid cells decreased the incidence of NASH development by decreasing steatosis, liver damage, monocyte infiltration, and the production of inflammatory chemokines. Our findings suggest that the increase of TNFα-producing Kupffer cells in the liver is crucial for the early phase of NASH development by promoting blood monocyte infiltration through the production of IP-10 and MCP-1.
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Tosello-Trampont AC, Landes SG, Nguyen V, Novobrantseva TI, Hahn YS. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J Biol Chem 2012. [PMID: 23066023 DOI: 10.10747/jbc.m112.417014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The mechanisms triggering nonalcoholic steatohepatitis (NASH) remain poorly defined. RESULTS Kupffer cells are the first responding cells to hepatocyte injuries, leading to TNFα production, chemokine induction, and monocyte recruitment. The silencing of TNFα in myeloid cells reduces NASH progression. CONCLUSION Increase of TNFα-producing Kupffer cells is crucial for triggering NASH via monocyte recruitment. SIGNIFICANCE Myeloid cells-targeted silencing of TNFα might be a tenable therapeutic approach. Nonalcoholic steatohepatitis (NASH), characterized by lipid deposits within hepatocytes (steatosis), is associated with hepatic injury and inflammation and leads to the development of fibrosis, cirrhosis, and hepatocarcinoma. However, the pathogenic mechanism of NASH is not well understood. To determine the role of distinct innate myeloid subsets in the development of NASH, we examined the contribution of liver resident macrophages (i.e. Kupffer cells) and blood-derived monocytes in triggering liver inflammation and hepatic damage. Employing a murine model of NASH, we discovered a previously unappreciated role for TNFα and Kupffer cells in the initiation and progression of NASH. Sequential depletion of Kupffer cells reduced the incidence of liver injury, steatosis, and proinflammatory monocyte infiltration. Furthermore, our data show a differential contribution of Kupffer cells and blood monocytes during the development of NASH; Kupffer cells increased their production of TNFα, followed by infiltration of CD11b(int)Ly6C(hi) monocytes, 2 and 10 days, respectively, after starting the methionine/choline-deficient (MCD) diet. Importantly, targeted knockdown of TNFα expression in myeloid cells decreased the incidence of NASH development by decreasing steatosis, liver damage, monocyte infiltration, and the production of inflammatory chemokines. Our findings suggest that the increase of TNFα-producing Kupffer cells in the liver is crucial for the early phase of NASH development by promoting blood monocyte infiltration through the production of IP-10 and MCP-1.
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46
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Gad YZ, Mouas N, Abdel-Aziz A, Abousmra N, Elhadidy M. Distinct immunoregulatory cytokine pattern in Egyptian patients with occult Hepatitis C infection and unexplained persistently elevated liver transaminases. Asian J Transfus Sci 2012; 6:24-8. [PMID: 22623838 PMCID: PMC3353624 DOI: 10.4103/0973-6247.95046] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background/Aim: The immunopathogenesis of occult Hepatitis C virus (HCV) infection is a matter of great controversy and has been suggested to involve a complex balance between cytokines with pro- and anti-inflammatory activity. This work aimed at studying the serum Th1 and Th2 cytokine production in patients with occult HCV infection. Materials and Methods: Serum levels of cytokines of Th1 (interleukin [IL]-2, INF-γ) and Th2 (IL-4) were measured in 27 patients with occult HCV infection and 28 patients with chronic hepatitis C infection. Results: The levels of IL-2 and interferon-γ were highly significantly increased in patients with chronic HCV infection (P<0.001). IL-4 was highly significantly increased in occult HCV infection (P<0.001). Significant increases were noted in chronic HCV infection regarding bilirubin (P<0.001), ALT (P = 0.009), AST (P = 0.013), AFP (P<0.001), while serum albumin was significantly higher in occult HCV infection (P<0.001). Necroinflammation (P<0.001), fibrosis (P<0.001), and cirrhosis (P = 0.03) were significantly increased in chronic HCV infection. Conclusion: Our data revealed a high prevalence of occult HCV infection (25%) in patients with unexplained persistently abnormal liver function test results. Those patients exhibited a distinct immunoregulatory cytokine pattern, favoring viral persistence and explaining the less aggressive course of this disease entity than chronic HCV infection.
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Affiliation(s)
- Yahia Z Gad
- Department of Internal Medicine, Mansoura University, Mansoura, Egypt
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Gad YZ, Ahmad NA, Mousa N, Farag RE, Abdel-Aziz AA, Abousmra NM, Elhadidy MA. Occult hepatitis C infection. EGYPTIAN LIVER JOURNAL 2012; 2:108-112. [DOI: 10.1097/01.elx.0000419586.77734.0d] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Ramos JA, Silva R, Hoffmann L, Ramos ALA, Cabello PH, Ürményi TP, Villella-Nogueira CA, Lewis-Ximenez L, Rondinelli E. Association of IL-10, IL-4, and IL-28B gene polymorphisms with spontaneous clearance of hepatitis C virus in a population from Rio de Janeiro. BMC Res Notes 2012; 5:508. [PMID: 22986179 PMCID: PMC3508811 DOI: 10.1186/1756-0500-5-508] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Accepted: 09/12/2012] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Cytokines play an important role in the regulation of the immune response. In hepatitis C virus (HCV) infection, cytokine levels may influence the outcome of acute HCV infection. Polymorphisms in cytokine genes have been associated to different expression levels in response to infection. This study was carried out to investigate the association of several cytokine gene polymorphisms with disease outcome in HCV-infected patients. FINDINGS Patients with chronic or spontaneously resolved HCV infection were included in a cross-sectional study. A comparative analysis was performed between the groups regarding frequency distribution of the following cytokines' gene polymorphisms: IL-10 (-1082 A/G; -819 T/C; -592 A/C), IL-4 (+33C/T), IFN-γ (+874 T/A), TNF-α (-238 G/A and -308 G/A) and IL-28B (rs12979860 C/T and rs8099917 T/G). RESULTS Eighteen patients with spontaneous viral clearance and 161 with chronic HCV infection were included. In the comparative analysis, the GG genotype of the IL-10 polymorphism -1082A/G was more frequent in patients with spontaneous viral clearance when compared to patients with chronic HCV (41.2% vs 6.2%; p = 0.001). This association was also found for the CC genotype of the IL-4 polymorphism +33C/T (72.2% vs 36.7%; p = 0.017) and the CC and TT genotypes of the IL-28B polymorphisms rs 12979860 and rs 8099917 (88.9% vs 30.3%; p < 0.001 and 88.9% vs 49.6%; p = 0.002). The IL10 (A-1082 G) and IL-28B (Crs12979860T) gene polymorphisms showed odds ratios of 12.848 and 11.077, respectively, and thus may have a greater influence on HCV spontaneous viral clearance. The IFN-γ (+874 T/A), TNF-α (-238 G/A and -308 G/A) polymorphisms did not show significant association with spontaneous viral clearance or chronicity. CONCLUSION The G allele for IL-10 (-1082 A/G), the C allele for IL-4 (+3 C/T) and the C and T alleles for IL-28B (rs12979860 and rs8099917, respectively) are associated with spontaneous viral clearance in hepatitis C infection.
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Affiliation(s)
- Juliene Antonio Ramos
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto Federal de Educação Ciência e Tecnologia do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rosane Silva
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto Nacional para Pesquisa Translacional em Saúde e Ambiente na Região Amazônica, Conselho Nacional de Desenvolvimento Científico e Tecnológico/MCT, Rio de Janeiro, Brazil
| | - Luísa Hoffmann
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ana Lucia Araújo Ramos
- Serviço de Hepatologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Turán Péter Ürményi
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Cristiane Alves Villella-Nogueira
- Serviço de Hepatologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Lia Lewis-Ximenez
- Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Edson Rondinelli
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto Nacional para Pesquisa Translacional em Saúde e Ambiente na Região Amazônica, Conselho Nacional de Desenvolvimento Científico e Tecnológico/MCT, Rio de Janeiro, Brazil
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Kohga K, Tatsumi T, Tsunematsu H, Aono S, Shimizu S, Kodama T, Hikita H, Yamamoto M, Oze T, Aketa H, Hosui A, Miyagi T, Ishida H, Hiramatsu N, Kanto T, Hayashi N, Takehara T. Interleukin-1β enhances the production of soluble MICA in human hepatocellular carcinoma. Cancer Immunol Immunother 2012; 61:1425-32. [PMID: 22302133 PMCID: PMC11028930 DOI: 10.1007/s00262-012-1208-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Accepted: 01/17/2012] [Indexed: 01/03/2023]
Abstract
The production of soluble major histocompatibility complex class I-related chain A (MICA) is thought to antagonize NKG2D-mediated immunosurveillance. Interleukin-1β (IL-1β) is elevated in patients with chronic hepatitis C (CH), and this might contribute to the escape of hepatocellular carcinoma (HCC) cells from innate immunity. In this study, we investigated the immunoregulatory role of IL-1β in the production of soluble MICA of HCC cells. First, we investigated the correlation between the serum IL-1β levels and soluble MICA in CH patients. Serum IL-1β levels were associated with soluble MICA levels in CH patients. The serum IL-1β levels of CH patients with the HCC occurrence were significantly higher than those of CH patients without HCC. We next examined the MICA production of IL-1β-treated HCC cells. Addition of IL-1β resulted in significant increase in the production of soluble MICA in HepG2 and PLC/PRF/5 cells, human HCC cells. But soluble MICA was not detected in both non-treated and IL-1β-treated normal hepatocytes. Addition of IL-1β did not increase the expressions of membrane-bound MICA on HCC cells. These were observed similarly in various cancer cells including a gastric cancer (MKN1), two colon cancers (HCT116 and HT29) and a cervical cancer (HeLa). Addition of IL-1β also increased the expression of a disintegrin and metalloproteinase (ADAM)9 in HCC cells, and the knockdown of ADAM9 in IL-1β-treated HCC cells resulted in the decrease in the production of soluble MICA of HCC cells. These findings indicate that IL-1β might enhance the production of soluble MICA by activating ADAM9 in human HCC.
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Affiliation(s)
- Keisuke Kohga
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Hinako Tsunematsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Satoshi Aono
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Satoshi Shimizu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Masashi Yamamoto
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Tsugiko Oze
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Hiroshi Aketa
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Atsushi Hosui
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Takuya Miyagi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Hisashi Ishida
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Tatsuya Kanto
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Norio Hayashi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
- Kansai-Rosai Hospital, Amagasaki, Hyogo, 660-8511 Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
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50
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Bala S, Tilahun Y, Taha O, Alao H, Kodys K, Catalano D, Szabo G. Increased microRNA-155 expression in the serum and peripheral monocytes in chronic HCV infection. J Transl Med 2012; 10:151. [PMID: 22846613 PMCID: PMC3477071 DOI: 10.1186/1479-5876-10-151] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 07/16/2012] [Indexed: 12/19/2022] Open
Abstract
Background Hepatitis C Virus (HCV), a single stranded RNA virus, affects millions of people worldwide and leads to chronic infection characterized by chronic inflammation in the liver and in peripheral immune cells. Chronic liver inflammation leads to progressive liver damage. MicroRNAs (miRNA) regulate inflammation (miR-155, -146a and -125b) as well as hepatocyte function (miR-122). Methods Here we hypothesized that microRNAs are dysregulated in chronic HCV infection. We examined miRNAs in the circulation and in peripheral monocytes of patients with chronic HCV infection to evaluate if specific miRNA expression correlated with HCV infection. Results We found that monocytes from chronic HCV infected treatment-naïve (cHCV) but not treatment responder patients showed increased expression of miR-155, a positive regulator of TNFα, and had increased TNFα production compared to monocytes of normal controls. After LPS stimulation, miR-155 levels were higher in monocytes from cHCV patients compared to controls. MiR-125b, which has negative regulatory effects on inflammation, was decreased in cHCV monocytes compared to controls. Stimulation of normal monocytes with TLR4 and TLR8 ligands or HCV core, NS3 and NS5 recombinant proteins induced a robust increase in both miR-155 expression and TNFα production identifying potential mechanisms for in vivo induction of miR-155. Furthermore, we found increased serum miR-155 levels in HCV patients compared to controls. Serum miR-125b and miR-146a levels were also increased in HCV patients. Serum levels of miR-122 were elevated in cHCV patients and correlated with increased ALT and AST levels and serum miR-155 levels. Conclusion In conclusion, our novel data demonstrate that miR-155, a positive regulator of inflammation, is upregulated both in monocytes and in the serum of patients with chronic HCV infection. Our study suggests that HCV core, NS3, and NS5 proteins or TLR4 and TLR8 ligands can mediate increased miR-155 and TNFα production in chronic HCV infection. The positive correlation between serum miR-155 and miR-122 increase in cHCV may be an indicator of inflammation-induced hepatocyte damage.
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Affiliation(s)
- Shashi Bala
- Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA
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