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Skrlec I, Talapko J. Hepatitis B and circadian rhythm of the liver. World J Gastroenterol 2022; 28:3282-3296. [PMID: 36158265 PMCID: PMC9346465 DOI: 10.3748/wjg.v28.i27.3282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/15/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
The circadian rhythm in humans is determined by the central clock located in the hypothalamus's suprachiasmatic nucleus, and it synchronizes the peripheral clocks in other tissues. Circadian clock genes and clock-controlled genes exist in almost all cell types. They have an essential role in many physiological processes, including lipid metabolism in the liver, regulation of the immune system, and the severity of infections. In addition, circadian rhythm genes can stimulate the immune response of host cells to virus infection. Hepatitis B virus (HBV) infection is the leading cause of liver disease and liver cancer globally. HBV infection depends on the host cell, and hepatocyte circadian rhythm genes are associated with HBV replication, survival, and spread. The core circadian rhythm proteins, REV-ERB and brain and muscle ARNTL-like protein 1, have a crucial role in HBV replication in hepatocytes. In addition to influencing the virus's life cycle, the circadian rhythm also affects the pharmacokinetics and efficacy of antiviral vaccines. Therefore, it is vital to apply antiviral therapy at the appropriate time of day to reduce toxicity and improve the effectiveness of antiviral treatment. For these reasons, understanding the role of the circadian rhythm in the regulation of HBV infection and host responses to the virus provides us with a new perspective of the interplay of the circadian rhythm and anti-HBV therapy. Therefore, this review emphasizes the importance of the circadian rhythm in HBV infection and the optimization of antiviral treatment based on the circadian rhythm-dependent immune response.
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Affiliation(s)
- Ivana Skrlec
- Department of Biophysics, Biology, and Chemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Jasminka Talapko
- Department of Anatomy Histology, Embryology, Pathology Anatomy and Pathology Histology, Faculty of Dental Medicine and Health, Osijek 31000, Croatia
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2
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Beringer A, Miossec P. IL-17 and IL-17-producing cells and liver diseases, with focus on autoimmune liver diseases. Autoimmun Rev 2018; 17:1176-1185. [PMID: 30321671 DOI: 10.1016/j.autrev.2018.06.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 06/05/2018] [Indexed: 02/07/2023]
Abstract
The pro-inflammatory cytokine interleukin(IL)-17 and IL-17-producing cells are important players in the pathogenesis of many autoimmune / inflammatory diseases. More recently, they have been associated with liver diseases. This review first describes the general knowledge on IL-17 and IL-17 producing cells. The second part describes the in vitro and in vivo effects of IL-17 on liver cells and the contribution of IL-17 producing cells to liver diseases. IL-17 induces immune cell infiltration and liver damage driving to hepatic inflammation and fibrosis and contributes to autoimmune liver diseases. The circulating levels of IL-17 and the frequency of IL-17-producing cells are elevated in a variety of acute and chronic liver diseases. The last part focuses on the effects of IL-17 deletion or neutralization in various murine models. Some of these observed beneficial effects suggest that targeting the IL-17 axis could be a new therapeutic strategy to prevent chronicity and progression of various liver diseases.
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Affiliation(s)
- Audrey Beringer
- Immunogenomics and Inflammation Research Unit EA4130, University of Lyon, Lyon, France
| | - Pierre Miossec
- Immunogenomics and Inflammation Research Unit EA4130, University of Lyon, Lyon, France.
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Xia Y, Jin X, Yu X, Li X, Du B, Liu Z, Shi Y, Li N, Zhang S. Expression profiles of transcription factors for special CD4+ T-cell subsets in peripheral blood mononuclear cells from patients with hepatitis B virus infection. Medicine (Baltimore) 2018; 97:e11438. [PMID: 30045265 PMCID: PMC6078757 DOI: 10.1097/md.0000000000011438] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
This study is to characterize the transcription factor expression profiles for the peripheral CD4 T-cell subsets, and analyze its associations with the clinical measures of the hepatitis B virus (HBV) infection.Totally 275 subjects were included. The expression levels of transcription factors (T-bet, GATA-3, Foxp3, RORγt, and Bcl-6) in the peripheral blood mononuclear cells (PBMCs) were determined by the real-time fluorimetry quantitative PCR (FQ-PCR).Lowest expression levels of all these transcription factors were observed for the HBsAb(-) group, which were higher in the HBsAb(+) and RHB groups. The T-bet/GATA-3 ratios in the CHB and RHB groups were significantly lower than the HBsAb(-) group, whereas the RORγt/Foxp3 ratios in the AHB and RHB groups were significantly higher than the CHB and HBsAb(+) groups. Furthermore, the RORγt mRNA expression levels were significantly different among groups with different disease severities or with different alanine aminotransferase (ALT) levels. The asymptomatic carrier (AsC) group and the group with ALT ≤ 40 had the highest express level. The mRNA expression levels of T-bet, GATA-3, Foxp3, and RORγt varied along with the aspartate aminotransferase (AST) levels, with AST ≤ 40 having the highest expression levels. In addition, significant differences were observed in the transcription factor expression levels between the group with the serum HBV DNA load of (1.000-9.999) × 10 copies/mL and other groups.Expression profile of critical transcription factors for peripheral CD4 T-cell subsets may indicate clinical outcomes of HBV infection.
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Affiliation(s)
- Yan Xia
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Xi Jin
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Xueyuan Yu
- Clinical Laboratory, the Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu
| | - Xingku Li
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Bo Du
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Zhen Liu
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Yuguang Shi
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Na Li
- Clinical Laboratory, Suihua First Hospital, Suihua, Heilongjiang, China
| | - Shuyun Zhang
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
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Wang LY, Fan YC, Zhao J, Ji XF, Wang K. Increased BATF expression is associated with the severity of liver damage in patients with chronic hepatitis B. Clin Exp Med 2018; 18:263-272. [PMID: 29164410 DOI: 10.1007/s10238-017-0480-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 11/12/2017] [Indexed: 12/29/2022]
Abstract
T helper (Th) 17 cells have a critical role in the pathogenesis of chronic hepatitis B virus (HBV) infection, and basic leucine zipper transcription factor, ATF-like (BATF) is a newly identified transcriptional factor regulating the differentiation of Th17 cells. However, its precise role in patients with chronic hepatitis B remains unclear. Sixty chronic hepatitis B (CHB) patients, twenty-two acute-on-chronic hepatitis B liver failure (ACHBLF) patients and seventeen healthy controls were included in our study. Both peripheral and intrahepatic expressions of BATF were analyzed by flow cytometry, quantitative real-time polymerase chain reaction and immunohistochemical staining. Peripheral BATF mRNA and protein expression levels were higher in CHB patients than those in healthy controls. Particularly in ACHBLF patients, the BATF mRNA and protein levels were further increased over those in CHB patients. Intrahepatic BATF-positive infiltrating cells were enriched in portal area of CHB patients, and more positive cells were found in patients with higher inflammation grade. Peripheral BATF expression was positively correlated with serum parameters of liver injury and plasma HBV DNA load. Furthermore, a positive correlation was found between the frequency of BATF-positive CD3+ T cells and the increased Th17 response in chronic HBV-infected patients. BATF over-expression might augment Th17 cell response and relate to the disease progression of CHB.
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Affiliation(s)
- Li-Yuan Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China
- Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan, 250012, China
| | - Jing Zhao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xiang-Fen Ji
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China.
- Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan, 250012, China.
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Paradowska-Gorycka A, Stypinska B, Pawlik A, Romanowska-Prochnicka K, Haladyj E, Manczak M, Olesinska M. RORC2 Genetic Variants and Serum Levels in Patients with Rheumatoid Arthritis. Int J Mol Sci 2016; 17:488. [PMID: 27043554 PMCID: PMC4848944 DOI: 10.3390/ijms17040488] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 03/17/2016] [Accepted: 03/21/2016] [Indexed: 01/17/2023] Open
Abstract
Background: In the present study, we aimed to evaluate whether polymorphisms within the RORc2 gene are involved in the risk and severity of rheumatoid arthritis (RA). Methods: 591 RA patients and 341 healthy individuals were examined for RORc2 gene polymorphisms. Serum retinoic acid receptor-related orphan receptor C (RORc) levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: The rs9826 A/G, rs12045886 T/C and rs9017 G/A RORc2 gene SNPs show no significant differences in the proportion of cases and control. Overall, rs9826 and rs9017 were in high linkage disequilibrium (LD) with D’ = 0.952 and r2 = 0.874, except rs9826 and rs12045886; and rs12045886 and rs9017 in weak LD. The genotype–phenotype analysis showed a significant association between RORc2 rs9826 A/G and rs9017 G/A single nucleotide polymorphisms (SNPs) and median of C-reactive protein (CRP). Serum RORc levels was higher in RA patients with rs9826AA, rs12045886TT and -TC, and rs9017AA genotypes compared to healthy subjects with the same genotypes (p = 0.02, p = 0.04 and p = 0.01, respectively). Moreover, the median of RORc protein level was higher in RA patients with number of swollen joints bigger then 3 (p = 0.04) and with Health Assessment Questionnaires (HAQ) score bigger then 1.5 (0.049). Conclusions: Current findings indicated that the RORc2 genetic polymorphism and the RORc2 protein level may be associated with severity of RA in the Polish population.
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Affiliation(s)
- Agnieszka Paradowska-Gorycka
- Department of Biochemistry and Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland.
| | - Barbara Stypinska
- Department of Biochemistry and Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland.
| | - Andrzej Pawlik
- Department of Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland.
| | - Katarzyna Romanowska-Prochnicka
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland.
| | - Ewa Haladyj
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland.
| | - Malgorzata Manczak
- Department of Epidemiology and Health Promotion, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland.
| | - Marzena Olesinska
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland.
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Zhou Q, Ding W, Jiang L, Xin J, Wu T, Shi D, Jiang J, Cao H, Li L, Li J. Comparative transcriptome analysis of peripheral blood mononuclear cells in hepatitis B-related acute-on-chronic liver failure. Sci Rep 2016; 6:20759. [PMID: 26861114 PMCID: PMC4748289 DOI: 10.1038/srep20759] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 01/07/2016] [Indexed: 12/16/2022] Open
Abstract
UNLABELLED Analysis of the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) is essential to elucidate the pathogenesis of HBV-ACLF and identify HBV-ACLF-specific biomarkers. In this study, high-throughput sequencing was performed to characterize the transcriptome of PMBCs from patients with HBV-ACLF. Specifically, 2381 differentially expressed genes (DEGs) and 776 differentially expressed transcripts were identified through comparisons with patients with chronic hepatitis B (CHB) and healthy controls. Gene Ontology (GO) analysis identified 114 GO terms that were clustered into 12 groups. We merged 10 dysregulated genes selected from these grouped GO terms and non-clustered terms with four significant genes with a specificity of >0.8 in the HBV-ACLF patients to obtain a set of 13 unique genes. The quantitative real-time polymerase chain reaction (qRT-PCR) validation of the top six genes (CYP19A1, SEMA6B, INHBA, DEFT1P, AZU1 and DEFA4) was consistent with the results of messenger ribonucleic acid (mRNA) sequencing. A further receiver operating characteristic (ROC) analysis revealed that the areas under the ROC curves of the six genes were all >0.8, which indicated their significant diagnostic potentials for HBV-ACLF. CONCLUSION The transcriptome characteristics of PBMCs are altered in patients with HBV-ACLF, and six genes may serve as biomarkers of HBV-ACLF.
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Affiliation(s)
- Qian Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Wenchao Ding
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Longyan Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Jiaojiao Xin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Tianzhou Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Dongyan Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Jing Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Hongcui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
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IL-17A in hepatitis B infection: friend or foe? Arch Virol 2014; 159:1883-8. [PMID: 24532300 DOI: 10.1007/s00705-014-2002-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 01/21/2014] [Indexed: 12/24/2022]
Abstract
Hepatitis B virus (HBV) is one of the most prevalent and infectious agents that leads to liver disease in humans. Five clinical forms of HBV infection exist, including fulminant, acute, chronic, asymptomatic and occult. The chronic, asymptomatic and occult forms are long-term infections that can lead to hepatocellular carcinoma (HCC) and liver cirrhosis. The mechanisms responsible for progression of these forms of the infection to HCC and liver cirrhosis are not yet clearly understood or characterised. However, genetic and immunological parameters may play important roles in the disease. IL-17A is an important cytokine involved in early immune responses against fungal and bacterial infections, but its role in the response against viral infections is yet to be fully clarified. The crucial roles of IL-17A in the pathogenesis of autoimmune and destructive immune-related diseases have been documented and may provide insights into its functions during hepatitis infection. Therefore, the aim of this review was to address the recent information regarding the status and association of IL-17A during hepatitis B infection and its related disorders, including HCC and liver cirrhosis.
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Xue ZM, Yao DM. Th17 cells and liver diseases. Shijie Huaren Xiaohua Zazhi 2013; 21:1185-1190. [DOI: 10.11569/wcjd.v21.i13.1185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In recent years, it has been demonstrated that T helper cells 17 (Th17) are closely related to the occurrence and development of many kinds of liver diseases such as viral hepatitis, autoimmune liver diseases and fatty liver diseases. Th17 cells are a new CD4+ T cell subset, which can interact with Th1, Th2 and Treg cells. There exists complex antagonistic or collaborative relationship among these cells. Understanding the role of Th17 cells in liver diseases will help explore the pathogenesis and treatment of these diseases.
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