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Zhang Z, Wang J, Li H, Niu Q, Tao Y, Zhao X, Zeng Z, Dong H. The role of the interleukin family in liver fibrosis. Front Immunol 2025; 16:1497095. [PMID: 39995661 PMCID: PMC11847652 DOI: 10.3389/fimmu.2025.1497095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 01/22/2025] [Indexed: 02/26/2025] Open
Abstract
Liver fibrosis represents a wound-healing response to chronic liver injury caused by viral infections, alcohol, and chemicals agents. It is a critical step in the progression from chronic liver disease to cirrhosis and hepatocellular carcinoma. No chemical or biological drugs have been approved for the treatment of liver fibrosis. Relevant studies have demonstrated that effective inhibition of hepatitis B virus (HBV) replication by nucleoside (acid) analogs or polyethylene glycol alpha-interferon can lead to recovery in some patients with hepatitis B liver fibrosis, However, some patients with liver fibrosis do not show improvement, even after achieving a complete serologic and virologic response. A similar situation occurs in patients with hepatitis C-related liver fibrosis. The liver, with its unique anatomical and immunological structure, is the largest immune organ and produces a large number of cytokines in response to external stimuli, which are crucial for the progression of liver fibrosis. cytokines can act either by directly affecting hepatic stellate cells (HSCs) or by indirectly regulating immune target cells. Among these, the interleukin family activates a complex cascade of responses, including cytokines, chemokines, adhesion molecules, and lipid mediators, playing a key role in the initiation and regulation of inflammation, as well as innate and adaptive immunity. In this paper, we systematically summarize recent literature to elucidate the pathogenesis of interleukin-mediated liver fibrosis and explore potential therapeutic targets for liver fibrosis treatment.
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Affiliation(s)
- Zixin Zhang
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiahui Wang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qun Niu
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yujing Tao
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xin Zhao
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zijian Zeng
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Haijian Dong
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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2
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Lin Y, Yan GJ, Liu MY, Cao Y, Zhang K, Wang N, Long FL, Mao DW. Review of the potential value of serum interleukin levels as prognostic biomarkers of liver failure. World J Clin Cases 2024; 12:6045-6056. [PMID: 39328855 PMCID: PMC11326103 DOI: 10.12998/wjcc.v12.i27.6045] [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] [Received: 03/28/2024] [Revised: 07/03/2024] [Accepted: 07/10/2024] [Indexed: 07/29/2024] Open
Abstract
Liver failure (LF) is prevalent in China and is characterized by complex pathogenesis, challenging clinical management, poor prognosis, and rising incidence and mortality rates. The immune status is an important factor affecting LF prognosis. Interleukins (Ils) are a type of cytokine that act and interact with multiple cells, including immune cells. These signaling molecules play important roles in intercellular information transmission, including the regulation of immune cells; mediation of the activation, proliferation, and differentiation of T and B cells; and orchestration of the inflammatory response. To date, many studies have explored the correlation between IL expression and liver disease prognosis, but few studies have evaluated Ils as the prognostic biomarkers of LF. This article reviews the potential use of Ils as the prognostic biomarkers of LF. Particularly, it evaluates the predictive values of IL-21, IL-22, and IL-31, the three often overlooked yet promising prognostic biomarkers, in predicting susceptibility to LF. Harnessing biomarkers for early prognostic insights can facilitate tailored treatment strategies and enhance patient survival. Thus, this article focuses on the identification of IL-21, IL-22, and IL-33 as biomarkers in preclinical and clinical studies on LF and reviews their role as biomarkers in the pathogenesis and diagnosis of LF.
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Affiliation(s)
- Yong Lin
- Graduate School, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
| | - Geng-Jie Yan
- Graduate School, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
| | - Mei-Yan Liu
- Graduate School, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
| | - Yin Cao
- Guangxi School of Chinese Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Kan Zhang
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Na Wang
- Department of Administration, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Fu-Li Long
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - De-Wen Mao
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
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3
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Ruta S, Grecu L, Iacob D, Cernescu C, Sultana C. HIV-HBV Coinfection-Current Challenges for Virologic Monitoring. Biomedicines 2023; 11:1306. [PMID: 37238976 PMCID: PMC10215721 DOI: 10.3390/biomedicines11051306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/21/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
HIV-HBV coinfected patients have higher rates of liver-related morbidity, hospitalizations, and mortality compared to HBV or HIV mono-infected ones. Clinical studies have shown an accelerated progression of liver fibrosis and an increased incidence of HCC, resulting from the combined action of HBV replication, immune-mediated hepatocytolysis, and HIV-induced immunosuppression and immunosenescence. Antiviral therapy based on dually active antiretrovirals is highly efficient, but late initiation, global disparities in accessibility, suboptimal regimens, and adherence issues may limit its impact on the development of end-stage liver disease. In this paper, we review the mechanisms of liver injuries in HIV-HBV coinfected patients and the novel biomarkers that can be used for treatment monitoring in HIV-HBV coinfected persons: markers that assess viral suppression, markers for liver fibrosis evaluation, and predictors of oncogenesis.
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Affiliation(s)
- Simona Ruta
- Virology Discipline, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
| | - Laura Grecu
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
| | - Diana Iacob
- Department for the Prevention and Control of Healthcare Associated Infections, Emergency University Hospital, 050098 Bucharest, Romania;
| | | | - Camelia Sultana
- Virology Discipline, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
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4
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Trinh QD, Pham NTK, Takada K, Ushijima H, Komine-Aizawa S, Hayakawa S. Roles of TGF-β1 in Viral Infection during Pregnancy: Research Update and Perspectives. Int J Mol Sci 2023; 24:ijms24076489. [PMID: 37047462 PMCID: PMC10095195 DOI: 10.3390/ijms24076489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/25/2023] [Accepted: 03/28/2023] [Indexed: 04/14/2023] Open
Abstract
Transforming growth factor-beta 1 (TGF-β1) is a pleiotropic growth factor playing various roles in the human body including cell growth and development. More functions of TGF-β1 have been discovered, especially its roles in viral infection. TGF-β1 is abundant at the maternal-fetal interface during pregnancy and plays an important function in immune tolerance, an essential key factor for pregnancy success. It plays some critical roles in viral infection in pregnancy, such as its effects on the infection and replication of human cytomegalovirus in syncytiotrophoblasts. Interestingly, its role in the enhancement of Zika virus (ZIKV) infection and replication in first-trimester trophoblasts has recently been reported. The above up-to-date findings have opened one of the promising approaches to studying the mechanisms of viral infection during pregnancy with links to corresponding congenital syndromes. In this article, we review our current and recent advances in understanding the roles of TGF-β1 in viral infection. Our discussion focuses on viral infection during pregnancy, especially in the first trimester. We highlight the mutual roles of viral infection and TGF-β1 in specific contexts and possible functions of the Smad pathway in viral infection, with a special note on ZIKV infection. In addition, we discuss promising approaches to performing further studies on this topic.
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Affiliation(s)
- Quang Duy Trinh
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Ngan Thi Kim Pham
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Kazuhide Takada
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Hiroshi Ushijima
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Shihoko Komine-Aizawa
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Satoshi Hayakawa
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
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Campos-Valdez M, Feustel S, Monroy-Ramírez HC, Barrientos-Salcedo C, Ayón-Pérez MF, Ramos-Márquez ME, Fernández-Galindo DA, Silva-Gómez JA, Santos A, Armendáriz-Borunda J, Sánchez-Orozco LV. Influence of C107R mutation from hepatitis B virus genotype H on in vitro hepatitis B surface antigen detection and IFN-β-1a treatment. Future Virol 2022. [DOI: 10.2217/fvl-2021-0347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: Assess the in vitro effect of hepatitis B virus (HBV) genotype H (HBV/H) with the small surface HBV protein (HBs) C107R mutation on hepatitis B surface antigen (HBsAg) detection, TGFB1, CAT and IFNB1A expression, and the response to IFN-β-1a treatment. Methods: HBV/H wild-type and HBs C107R variant replicons were constructed and transfected into hepatic stellate cells and/or Huh7 that were later treated with IFN-β-1a. HBsAg, HBV-DNA, pgRNA, TGFB1, CAT and IFNB1A expression was analyzed. 3D HBs structure from wild-type and C107R were foreseen by AlphaFold protein predictor, and IFN-β-1a antiviral effect was evaluated. Results: C107R mutation did not impact viral replication, but HBsAg serologic detection was affected. Wild-type and C107R similarly modified gene expression and responded to IFN-β-1a. Conclusion: C107R disrupts the Cys107/Cys138 disulfide bond and impairs HBsAg detection. Independently of the mutation, there were changes in TGFB1, CAT and IFNB1A expression, and a medium response to IFN-β-1a treatment compared with genotype A and C.
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Affiliation(s)
- Marina Campos-Valdez
- Instituto de Biología Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, 44340, México
| | - Sina Feustel
- Instituto de Biología Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, 44340, México
| | - Hugo Christian Monroy-Ramírez
- Instituto de Biología Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, 44340, México
| | - Carolina Barrientos-Salcedo
- Laboratorio de Química Médica y Quimiogenómica, Facultad de Bioanálisis, Universidad Veracruzana, Veracruz, México
| | | | - Martha Eloísa Ramos-Márquez
- Instituto de Enfermedades Crónico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, 44340, México
| | - David A Fernández-Galindo
- Instituto de Biología Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, 44340, México
| | - Jorge Antonio Silva-Gómez
- Instituto de Biología Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, 44340, México
| | - Arturo Santos
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Campus Guadalajara, Zapopan, Jalisco, 45201, México
| | - Juan Armendáriz-Borunda
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Campus Guadalajara, Zapopan, Jalisco, 45201, México
| | - Laura Verónica Sánchez-Orozco
- Instituto de Biología Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, 44340, México
- Instituto de Enfermedades Crónico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, 44340, México
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Serum Interleukins as Potential Prognostic Biomarkers in HBV-Related Acute-on-Chronic Liver Failure. Mediators Inflamm 2022; 2022:7794890. [PMID: 36117587 PMCID: PMC9477565 DOI: 10.1155/2022/7794890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/06/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is relatively common in China and has complex pathogenesis, difficult clinical treatment, and poor prognosis. Immune status is an important factor affecting ACLF prognosis. Interleukins are a family of secreted lymphocyte factors that interact with a host of cell types including immune cells. These signaling molecules play important roles in transmitting information; regulating immune cells; mediating the activation, proliferation, and differentiation of T and B cells; and modulating inflammatory responses. Many studies have investigated the correlation between interleukin expression and the prognosis of HBV-ACLF. This review focuses on the potential use of interleukins as prognostic biomarkers in HBV-ACLF. References were mainly identified through PubMed and CNKI search, including relevant studies published until December 2021. We have summarized reports of several promising diagnostic interleukin biomarkers that predict susceptibility to HBV-ACLF. The use of biomarkers to understand early prognosis can help devise different therapeutic measures and improve patient survival. Ongoing research on prognostic biomarkers of HBV-ACLF is promising, and future preclinical and clinical studies are warranted.
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7
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Lefeuvre C, Roux M, Blanchard S, Le Guillou-Guillemette H, Boursier J, Lunel-Fabiani F, Jeannin P, Pivert A, Ducancelle A. Analysis of hepatic fibrosis markers in the serum of chronic hepatitis B patients according to basal core promoter/precore mutants. Sci Rep 2022; 12:10261. [PMID: 35715541 PMCID: PMC9205978 DOI: 10.1038/s41598-022-14285-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 06/03/2022] [Indexed: 12/29/2022] Open
Abstract
The A1762T/G1764A double mutant in the basal core promoter (BCP) region of the hepatitis B virus (HBV) is associated with severe hepatic lesions while the G1899A mutation with the double mutant is associated with a significant reduction in the risk of severe fibrosis. This study aims to measure a number of markers in the serum of patients with chronic HBV infection and to assess relationships between these markers and BCP/precore mutants with consideration of the stage of fibrosis. The serum levels of resistin, TGF-β1, MMP-1, TIMP-1, collagen IA1 and PDGF-BB, which are markers that are known to be involved in the process of hepatic fibrosis, were assayed. The serum levels of PDGF-BB and TIMP-1, and the mutation profile were independently associated with advanced fibrosis. A higher level of TIMP-1 was associated with advanced fibrosis regardless of the mutation status, and a higher level of PDGF-BB was associated with nonsevere fibrosis in patients infected with viruses harboring the A1762T/G1764A or A1762T/G1764A/G1899A mutations. Our results suggest an impact of the A1762T/G1764A mutant on the biological pathway related to TGF-β1 and PDGF-BB. In vitro studies are needed to understand the impact of these mutants on the serum secretion of markers involved in fibrosis severity.
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Affiliation(s)
| | - Marine Roux
- Univ Angers, HIFIH, SFR ICAT, F-49000, Angers, France
| | - Simon Blanchard
- Univ Angers, INSERM Unité 892, CNRS Unit 6299, F-49000, Angers, France
| | | | - Jérôme Boursier
- Univ Angers, CHU Angers, HIFIH, SFR ICAT, F-49000, Angers, France
| | | | - Pascale Jeannin
- Univ Angers, INSERM Unité 892, CNRS Unit 6299, F-49000, Angers, France
| | - Adeline Pivert
- Univ Angers, CHU Angers, HIFIH, SFR ICAT, F-49000, Angers, France
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8
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IL-31: State of the Art for an Inflammation-Oriented Interleukin. Int J Mol Sci 2022; 23:ijms23126507. [PMID: 35742951 PMCID: PMC9223565 DOI: 10.3390/ijms23126507] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/06/2022] [Accepted: 06/08/2022] [Indexed: 12/23/2022] Open
Abstract
Interleukin 31 belongs to the IL-6 superfamily, and it is an itch mediator already studied in several diseases, comprising atopic dermatitis, allergic pathologies, and onco-hematological conditions. This research aims to assess the role of this cytokine in the pathogenesis of these conditions and its potential therapeutic role. The research has been conducted on articles, excluding reviews and meta-analysis, both on animals and humans. The results showed that IL-31 plays a crucial role in the pathogenesis of systemic skin manifestations, prognosis, and itch severity. Traditional therapies target this interleukin indirectly, but monoclonal antibodies (Mab) directed against it have shown efficacy and safety profiles comparable with biological drugs that are already available. Future perspectives could include the development of new antibodies against IL-31 both for humans and animals, thus adding a new approach to the therapy, which often has proven to be prolonged and specific for each patient.
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9
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Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis. Nat Commun 2021; 12:5947. [PMID: 34642338 PMCID: PMC8511151 DOI: 10.1038/s41467-021-26099-w] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 09/13/2021] [Indexed: 11/29/2022] Open
Abstract
Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc. Systemic sclerosis (SSc) disease involves multisystem fibrosis and autoimmunity with limited treatment options. Here the authors demonstrate that IL-31 and IL-31RA are overexpressed in dermal fibroblasts from SSc patients and show that fibrosis and cytokine release can be reduced upon blocking of IL-31/IL-31RA.
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10
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Identification of plasma lncRNA-ATB levels in hepatitis B virus-related cirrhosis and non-cirrhotic chronic hepatitis B patients. Virus Res 2021; 303:198503. [PMID: 34331990 DOI: 10.1016/j.virusres.2021.198503] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 12/19/2022]
Abstract
Long non-coding RNA-ATB (LncRNA-ATB) which is activated by transforming growth factor-β (TGF-β), is a key regulator of TGF-β signaling pathway. TGF-β plays an important role in various pathogenic processes, from inflammation and fibrosis to cirrhosis and cancer. In this study, we evaluated the plasma levels of lncRNA-ATB in patients with hepatitis B virus (HBV)-related cirrhosis and non-cirrhotic patients with chronic hepatitis B (CHB) and investigated the clinical values. Plasma samples were collected from 44 HBV-related cirrhosis patients, 45 non-cirrhotic CHB and 75 healthy controls. Briefly, after total RNA extraction and cDNA synthesis, quantitative real-time PCR (qPCR) was performed to detect plasma lncRNA-ATB levels. Results show the plasma levels of lncRNA-ATB in HBV-related cirrhosis patients were significantly higher in comparison to healthy controls (Fold change=2.60, p value=0.04). Also, we determined plasma levels of lncRNA-ATB as a specific biomarker of HBV-related cirrhosis (AUC=0.65, p value=0.03, Sensitivity 61.36%; Specificity 70.00%). In addition to, we investigated the plasma levels of lncRNA-ATB in non-cirrhotic CHB patients were significantly lower than healthy controls (Fold change= 0.33, p value=0.01). We also indicated plasma lncRNA-ATB levels were as a sensitive biomarker for diagnosis of non-cirrhotic CHB patients compared with healthy (AUC=0.66, p value=0.00, Sensitivity 71.11%; Specificity 57.78%). According to our results, circulating lncRNA-ATB has good specificity for diagnosing hepatitis B virus (HBV)-related cirrhosis and good sensitivity for diagnosis of non-cirrhotic chronic hepatitis B (CHB) patients.
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11
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Campos-Valdez M, Monroy-Ramírez HC, Armendáriz-Borunda J, Sánchez-Orozco LV. Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability. Viruses 2021; 13:v13061167. [PMID: 34207116 PMCID: PMC8235420 DOI: 10.3390/v13061167] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/16/2022] Open
Abstract
The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.
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Affiliation(s)
- Marina Campos-Valdez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Hugo C. Monroy-Ramírez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Juan Armendáriz-Borunda
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Campus Guadalajara, Zapopan 45201, Jalisco, México
| | - Laura V. Sánchez-Orozco
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Correspondence: ; Tel.: +52-33-3954-5677
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12
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Interleukin-31 and Pruritic Skin. J Clin Med 2021; 10:jcm10091906. [PMID: 33924978 PMCID: PMC8124688 DOI: 10.3390/jcm10091906] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/26/2022] Open
Abstract
Skin inflammation often evokes pruritus, which is the major subjective symptom in many inflammatory skin diseases such as atopic dermatitis and prurigo nodularis. Pruritus or itch is a specific sensation found only in the skin. Recent studies have stressed the pivotal role played by interleukin-31 (IL-31) in the sensation of pruritus. IL-31 is produced by various cells including T helper 2 cells, macrophages, dendritic cells and eosinophils. IL-31 signals via a heterodimeric receptor composed of IL-31 receptor A (IL-31RA) and oncostatin M receptor β. Recent clinical trials have shown that the anti-IL-31RA antibody nemolizumab can successfully decrease pruritus in patients with atopic dermatitis and prurigo nodularis. The IL-31 pathway and pruritic skin are highlighted in this review article.
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Yombo DJK, Odayar V, Gupta N, Jegga AG, Madala SK. The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis. Front Immunol 2021; 12:645717. [PMID: 33815402 PMCID: PMC8017338 DOI: 10.3389/fimmu.2021.645717] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
Abstract
Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 Th2 T cells, but its signaling receptor IL-31RA is primarily expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31RA deficiency in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including extracellular matrix and epithelial cell-associated gene networks. Furthermore, the lungs of human IPF showed an elevated expression of IL-31 when compared to healthy subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. Thus, therapeutic targeting the IL-31-IL-31RA axis may prevent collagen deposition, improve lung function, and have therapeutic potential in pulmonary fibrosis.
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Affiliation(s)
- Dan J K Yombo
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Varshini Odayar
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Nishant Gupta
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Anil G Jegga
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, United States.,Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Satish K Madala
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
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14
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Li X, Liu X, Wang W. IL-35: A Novel Immunomodulator in Hepatitis B Virus-Related Liver Diseases. Front Cell Dev Biol 2021; 9:614847. [PMID: 33777929 PMCID: PMC7990793 DOI: 10.3389/fcell.2021.614847] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 02/19/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a risk factor for liver cirrhosis (LC) and hepatocellular carcinoma (HCC), however, little is known about the mechanisms involved in the progression of HBV-related diseases. It has been well acknowledged that host immune response was closely related to the clinical outcomes of patients with HBV infection. As the factors closely related to the immunomodulatory process, cytokines are crucial in the cell-cell communication and the host responses to HBV infection. Recently, a newly discovered cytokine, designated as interleukin-35 (IL-35), has been proved to be essential for the progression of chronic HBV infection, the development of cirrhosis, the transformation of cirrhosis to HCC, and the metastasis of HCC. Specifically, it showed various biological activities such as inhibiting the HBV-specific cytotoxic T lymphocyte (CTL) proliferation and cytotoxicity, deactivating the immature effector T-cells (Teffs), as well as delaying the proliferation of dendritic cells. It regulated the immune responses by acting as a “brake” on the activation of Teffs, which subsequently played important roles in the pathogenesis of various inflammatory diseases and malignancies. In this review, we focused on the most recent data on the relationship between IL-35 and chronic HBV infection, LC and HCC.
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Affiliation(s)
- Xuefen Li
- Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xia Liu
- Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, China
| | - Weilin Wang
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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15
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Kabashima K, Irie H. Interleukin-31 as a Clinical Target for Pruritus Treatment. Front Med (Lausanne) 2021; 8:638325. [PMID: 33644103 PMCID: PMC7906974 DOI: 10.3389/fmed.2021.638325] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 01/14/2021] [Indexed: 12/22/2022] Open
Abstract
In recent years, the published literature has suggested the key involvement of the cytokine interleukin-31 (IL-31) in the symptomatology of pruritus, and both IL-31 and its receptor have become potential therapeutic targets for a range of pruritic diseases. Elevated levels of IL-31 or its receptor have been reported in the tissue or serum of patients with pruritic skin diseases, such as atopic dermatitis, prurigo nodularis, and psoriasis. Pruritus places a heavy burden on patients, and can have a negative impact on daily life, sleep, and mental health. Since current anti-pruritic treatments are often ineffective, affected patients are in urgent need of new therapies. As a result, drug development targeting the IL-31 pathway is evolving rapidly. To date, only nemolizumab, a humanized monoclonal antibody targeting the IL-31 receptor, has successfully completed late-stage clinical studies. This article will highlight our current clinical understanding of the role of IL-31 in pruritic disease, and explore recent progress in drug development as well as the anticipated future advances in this field.
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Affiliation(s)
- Kenji Kabashima
- Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Irie
- Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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16
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Hu S, Lian PP, Hu Y, Zhu XY, Jiang SW, Ma Q, Li LY, Yang JF, Yang L, Guo HY, Zhou H, Yang CC, Meng XM, Li J, Li HW, Xu T, Zhou H. The Role of IL-35 in the Pathophysiological Processes of Liver Disease. Front Pharmacol 2021; 11:569575. [PMID: 33584256 PMCID: PMC7873894 DOI: 10.3389/fphar.2020.569575] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 12/10/2020] [Indexed: 12/23/2022] Open
Abstract
It is known that liver diseases have several characteristics of massive lipid accumulation and lipid metabolic disorder, and are divided into liver inflammation, liver fibrosis, liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in patients. Interleukin (IL)-35, a new-discovered cytokine, can protect the liver from the environmental attack by increasing the ratio of Tregs (T regulatory cells) which can increase the anti-inflammatory cytokines and inhibit the proliferation of immune cellular. Interestingly, two opposite mechanisms (pro-inflammatory and anti-inflammatory) have connection with the ultimate formation of liver diseases, which suggest that IL-35 may play crucial function in the process of liver diseases through immunosuppressive regulation. Besides, some obvious advantages also imply that IL-35 can be considered as a new therapeutic target to control the progression of liver diseases, while its mechanism of function still needs further research.
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Affiliation(s)
- Shuang Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Pan-Pan Lian
- School of Pharmacy, NanJing University, NanJing, China
| | - Ying Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xing-Yu Zhu
- National Drug Clinical Trial Institution, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Shao-Wei Jiang
- The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiang Ma
- Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Liang-Yun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jun-Fa Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Li Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Hai-Yue Guo
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Hong Zhou
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Chen-Chen Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Hai-Wen Li
- The Third Affiliated Hospital of Anhui Medical University, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Huan Zhou
- National Drug Clinical Trial Institution, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
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17
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Mu N, Lin F, Jiang Z, Liang Y, Yang Z. Implication of Increased Serum IL-31 for Primary Biliary Cholangitis. Immunol Invest 2020; 50:662-670. [PMID: 32613870 DOI: 10.1080/08820139.2020.1785490] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Interleukin-31 (IL-31) has diverse biological functions. Increased IL-31 has been found in some skin and autoimmune diseases. There has been no study reporting the association between IL-31 and primary biliary cholangitis (PBC). This study was designed to determine serum IL-31 level and to explore its diagnostic value for PBC as well as the association of IL-31 with inflammatory and fibrotic progression. 60 PBC patients, 32 age- and sex-matched patients with chronic hepatitis B (CHB) and 30 age- and sex-matched healthy controls (HC) were recruited. The sera were detected for IL-31, IL-4, interferon gamma (IFN-γ), IL-17 and other laboratory indicators. Serum IL-31 levels were significantly higher in PBC patients (median, IQR, 20.6, 16.7-26.2, pg/ml) than CHB patients (median, IQR, 11.3, 8.0-13.0, pg/ml) and HC (median, IQR, 11.0, 10.0-12.2 pg/ml) (P < .001). Serum IL-31 performed well for identifying PBC, especially for antimitochondrial antibodies (AMA)-negative PBC with AUC of 0.900, optimal cutoff value of 13.6 pg/ml, sensitivity of 87.5% and specificity of 83.9%. Serum IL-31 was positively correlated with platelet count (r = 0.368, P = .004), but negatively with FIB4 (r = -0.307, P = .017) and histological stages (r = -0.364, P = .004) in PBC patients. It was also significantly correlated with IFN-γ (r = 0.404, P = .001) and IL-4 (r = 0.291, P = .026), but not with IL-17 (r = 0.151, P = .259) in PBC patients. Serum IL-31 is increased in and may be a useful marker for PBC, in particular, for AMA-negative PBC. Furthermore, it is inversely associated with fibrotic progression of PBC.
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Affiliation(s)
- Ning Mu
- Department of General Surgery, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang, China
| | - Feng Lin
- Department of General Surgery, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang, China
| | - Zhiguo Jiang
- Department of General Surgery, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang, China
| | - Yan Liang
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zaixing Yang
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang, China
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18
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Cao S, Zhu L, Zhu C, Feng J, Yin J, Lu J, Xu Y, Yang H, Huang Y, Zhang Q. Helicobacter hepaticus infection-induced IL-33 promotes hepatic inflammation and fibrosis through ST2 signaling pathways in BALB/c mice. Biochem Biophys Res Commun 2020; 525:654-661. [PMID: 32122655 DOI: 10.1016/j.bbrc.2020.02.139] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 02/23/2020] [Indexed: 12/14/2022]
Abstract
It has been documented that Helicobacter hepaticus (H. hepaticus) infection is linked to hepatic inflammation and fibrosis. Interleukin 33 (IL-33) is a cytokine involved in inflammatory and fibrotic diseases, but its relevance to H. hepaticus infection-induced liver inflammation and fibrosis is unknown. In this study, we found that the expression of IL-33 in mice liver was significantly induced by H. hepaticus infection at 24 weeks post infection (WPI). Immunohistochemistry analysis revealed that IL-33 was transferred from the nucleus to the cytoplasm due to infection. The quantitation of inflammatory cytokine and histopathology evaluation showed that IL-33 knockdown attenuated the H. hepaticus-induced hepatic inflammation and fibrosis. More importantly, H. hepaticus promoted the expression of the IL-33 receptor ST2 on cell surfaces, and the expression of ST2 then activated the expression nuclear factor-κB (p65), α-SMA, and Erk1/2. These observations provide novel insights into the pathogenic mechanism of hepatic inflammation and fibrosis during H. hepaticus infection.
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Affiliation(s)
- Shuyang Cao
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Liqi Zhu
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Chen Zhu
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Jie Feng
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China; Shanghai Lab Animal Research Center, Shanghai, 201203, China
| | - Jun Yin
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Jin Lu
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu Province, 214064, China; Public Health Research Center, Jiangnan University, Wuxi, 214122, Jiangsu Province, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yongliang Xu
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu Province, 214064, China; Public Health Research Center, Jiangnan University, Wuxi, 214122, Jiangsu Province, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Haitao Yang
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu Province, 214064, China; Public Health Research Center, Jiangnan University, Wuxi, 214122, Jiangsu Province, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yuzheng Huang
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu Province, 214064, China; Public Health Research Center, Jiangnan University, Wuxi, 214122, Jiangsu Province, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Quan Zhang
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, 225009, Jiangsu, China.
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19
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Ganesan M, Poluektova LY, Kharbanda KK, Osna NA. Human immunodeficiency virus and hepatotropic viruses co-morbidities as the inducers of liver injury progression. World J Gastroenterol 2019; 25:398-410. [PMID: 30700937 PMCID: PMC6350175 DOI: 10.3748/wjg.v25.i4.398] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/15/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatotropic viruses induced hepatitis progresses much faster and causes more liver- related health problems in people co-infected with human immunodeficiency virus (HIV). Although treatment with antiretroviral therapy has extended the life expectancy of people with HIV, liver disease induced by hepatitis B virus (HBV) and hepatitis C virus (HCV) causes significant numbers of non-acquired immune deficiency syndrome (AIDS)-related deaths in co-infected patients. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV/HCV and HIV/HBV co-infections have been reported. In this paper, we review recent studies examining the natural history and pathogenesis of liver disease in HIV-HCV/HBV co-infection in the era of direct acting antivirals (DAA) and antiretroviral therapy (ART). We also review the novel therapeutics for management of HIV/HCV and HIV/HBV co-infected individuals.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Larisa Y Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
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20
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Abstract
Oncostain M, a member of the IL-6 family of cytokines, is produced by immune cells in response to infections and tissue injury. OSM has a broad, often context-dependent effect on various cellular processes including differentiation, hematopoiesis, cell proliferation, and cell survival. OSM signaling is initiated by binding to type I (LIFRβ/gp130) or type II (OSMRβ/gp130) receptor complexes and involves activation of Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase, and phosphatidylinositol-3-kinase. High levels of OSM have been detected in many chronic inflammatory conditions characterized by fibrosis, giving a rationale to target OSM for the treatment of these diseases. Here we discuss the current knowledge on the role of OSM in various stages of the fibrotic process including inflammation, vascular dysfunction, and activation of fibroblasts.
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Affiliation(s)
| | - Maria Trojanowska
- Corresponding Author: Maria Trojanowska, Boston University School of Medicine, 72 East Concord St, E-5, Boston, MA 02118, Tel.: 617-638-4318; Fax: 617-638-5226
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21
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Kim HJ, Zeidi M, Bonciani D, Pena SM, Tiao J, Sahu S, Werth VP. Itch in dermatomyositis: the role of increased skin interleukin-31. Br J Dermatol 2018; 179:669-678. [PMID: 29494763 DOI: 10.1111/bjd.16498] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Interleukin (IL)-31 is implicated in pruritus associated with pruritic skin diseases like atopic dermatitis. Although pruritus is a prominent feature in dermatomyositis (DM), few studies have evaluated the pathogenesis of DM-associated itch. OBJECTIVES To establish the prevalence of itch in DM, and to investigate the role of IL-31 in DM-related itch. METHODS Pruritus and disease activity of DM were evaluated by a visual analogue scale (VAS) and the Cutaneous Disease and Activity Severity Index (CDASI), respectively. Expression of IL-31 and IL-31 receptor alpha (IL-31RA) in lesional DM, nonlesional DM and healthy control skin was evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunofluorescence. Flow cytometry was performed on skin cells isolated from lesional DM skin to identify cellular sources of IL-31 in DM. RESULTS Among 191 patients with DM, 50·8% had moderate-to-severe itch, and itch was correlated with increased cutaneous severity (r = 0·34). In patients with itchy DM, gene expression of IL31 and IL31RA in lesional skin was upregulated compared with nonlesional skin and healthy control skin. IL31 mRNA expression positively correlated with VAS itch score (r = 0·67). On immunofluorescence, immunoreactivity for IL-31 and IL-31RA was stronger in lesional skin. Flow cytometry showed that lesional DM skin contained significantly more IL-31-producing cells, and CD4+ cells were the most common cell type. Lenabasum, an emerging treatment for DM, significantly downregulated IL-31 from CpG-stimulated peripheral blood mononuclear cells. CONCLUSIONS Increased skin IL-31 may play a role in DM-associated itch, and ongoing trials will evaluate the effects of systemic treatment on IL-31 and itch in DM.
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Affiliation(s)
- H J Kim
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, U.S.A.,Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, U.S.A.,Department of Dermatology, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - M Zeidi
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, U.S.A.,Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, U.S.A
| | - D Bonciani
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, U.S.A.,Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, U.S.A.,Department of Surgery and Translational Medicine, Section of Dermatology, University of Florence, Florence, Italy
| | - S M Pena
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, U.S.A
| | - J Tiao
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, U.S.A.,Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, U.S.A
| | - S Sahu
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, U.S.A.,Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, U.S.A
| | - V P Werth
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, U.S.A.,Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, U.S.A
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22
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CXCL10-induced IL-9 promotes liver fibrosis via Raf/MEK/ERK signaling pathway. Biomed Pharmacother 2018; 105:282-289. [PMID: 29860220 DOI: 10.1016/j.biopha.2018.05.128] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 05/20/2018] [Accepted: 05/24/2018] [Indexed: 12/21/2022] Open
Abstract
Liver fibrosis is a typical complication of chronic liver diseases resulting in cirrhosis that remains a major public health problem. The aim of the present study was to identify the role of interleukin-9 (IL-9), an important regulator of inflammation and autoimmune diseases, in hepatic fibrosis progression. It was found that the expression of IL-9 was significantly increased in liver tissues of liver cirrhosis patients compared with that in healthy controls. Moreover, CXCL10, not CXCL9 or CXCL11, induced IL-9 expression in the liver tissue. Overexpression of IL-9 enhanced the severity of liver fibrosis in the carbon tetrachloride (CCl4)-induced liver fibrosis model. Western Blotting analysis revealed that this pro-fibrosis bioactivity of IL-9 was attributed to its selective activation of Raf/MEK/ERK signaling. Finally, administration of neutralizing anti-IL-9 antibody ameliorated liver fibrosis and attenuated the activation of hepatic stellate cells in mice. All these findings indicate that IL-9 plays a deleterious role in the development and progression of liver fibrosis, and IL-9 based immunotherapy may prove to be a promising strategy for the treatment of liver fibrosis.
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23
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Wu X, Su Z, Cai B, Yan L, Li Y, Feng W, Wang L. Increased Circulating Follicular Regulatory T-Like Cells May Play a Critical Role in Chronic Hepatitis B Virus Infection and Disease Progression. Viral Immunol 2018; 31:379-388. [PMID: 29683413 DOI: 10.1089/vim.2017.0171] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Affiliation(s)
- Xiaojuan Wu
- Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University , Chengdu, Sichuan Province, China
| | - Zhenzhen Su
- Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University , Chengdu, Sichuan Province, China
| | - Bei Cai
- Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University , Chengdu, Sichuan Province, China
| | - Lin Yan
- Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University , Chengdu, Sichuan Province, China
| | - Yamei Li
- Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University , Chengdu, Sichuan Province, China
| | - Weihua Feng
- Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University , Chengdu, Sichuan Province, China
| | - Lanlan Wang
- Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine, West China Hospital of Sichuan University , Chengdu, Sichuan Province, China
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Zhang J, Ma J, Wang H, Li J. Correlation between cortisol levels and concurrent infection for hepatitis B cirrhosis patients and countermeasure analysis. Exp Ther Med 2018; 15:2951-2955. [PMID: 29456701 PMCID: PMC5795706 DOI: 10.3892/etm.2018.5738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 12/13/2017] [Indexed: 11/29/2022] Open
Abstract
The study assessed the correlation between cortisol (COR) levels and concurrent infection for the patients with hepatitis B cirrhosis for corresponding countermeasure analysis. In total, 86 patients with hepatitis B cirrhosis (non-infection group) and 32 patients with hepatitis B cirrhosis complicated with infection (infection group) who were diagnosed and treated in the Beijing YouAn Hospital from March 2014 to March 2017 were selected. The fasting venous blood of all the patients was drawn to detect COR, cortisol binding globulin (CBG), blood routine indexes, C-reactive protein (CRP), procalcitonin (PCT), endotoxin and other indicators. The relative expression of CBG mRNA was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The differences and correlation of COR levels between the infection and non-infection groups were compared and analyzed. The concentrations of COR and CBG were decreased with the increase of Child-Pugh grade, and the difference was statistically significant (P<0.05). COR, CBG and free cortisol (FC) concentrations with the same Child-Pugh grade in the non-infection group were higher than those in the infection group (P<0.05). COR, CBG and FC concentrations of abdominal infection complicated with sepsis or abdominal infection complicated with pulmonary infection were lower than those of simple abdominal infection (P<0.05). The relative expression of CBG mRNA was detected by RT-qPCR, which also showed that: for Child-Pugh grade, grade A > grade B > grade C (P<0.05), non-infection group > infection group (P<0.05), abdominal infection + sepsis group and abdominal infection + pulmonary infection group were lower than the simple abdominal infection group (P<0.05). The values of white blood cells (WBC), neutrophils, CRP, PCT and endotoxin in the infection group were higher than those in the non-infection group, and the differences were statistically significant (P<0.05). COR, CGB and FC were negatively correlated with inflammatory indexes such as WBC, neutrophils, CRP, PCT and endotoxin. The r value of COR and FC in the non-infection group was 0.678, while that of OR and FC in the infection group was 0.787. COR was positively correlated with FC before and after infection. The results of the study show that the cortisol levels of patients with hepatitis B cirrhosis are significantly correlated with whether infected or not, levels of disease condition and infection types, and can be used as sensitive indicators of hepatitis B cirrhosis infection.
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Affiliation(s)
- Jian Zhang
- Department of Emergency, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Junwei Ma
- Department of Emergency, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Hongxin Wang
- Department of Emergency, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Junhong Li
- Department of Emergency, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
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Liu Y, Xu Y, Ma H, Wang B, Xu L, Zhang H, Song X, Gao L, Liang X, Ma C. Hepatitis B virus X protein amplifies TGF-β promotion on HCC motility through down-regulating PPM1a. Oncotarget 2018; 7:33125-35. [PMID: 27121309 PMCID: PMC5078080 DOI: 10.18632/oncotarget.8884] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 04/02/2016] [Indexed: 12/26/2022] Open
Abstract
Over-activation of transforming growth factor-β (TGF-β) signaling pathway promotes cell migration and invasion in hepatocellular carcinoma (HCC). The Hepatitis B virus X protein (HBx) is involved in the enhancement of TGF-β signaling pathway in HCC while the mechanism remains unclear. Protein phosphatase magnesium dependent 1A (PPM1a) functions as a phosphatase essential for terminating the TGF-β signaling pathway by dephosphorylating p-Smad2/3. In this study, we found that HBx dose-dependently downregulated PPM1a protein level in the presence of TGF-β, while having no effect on its mRNA level. Further study showed that HBx increased the ubiquitination of PPM1a and accelerated its proteasomal degradation. Restoration of PPM1a almost completely abrogated HBx mediated promotion on HCC migration and invasion. This involvement of PPM1a in HBx-related HCC was further confirmed with immunohistochemical analysis in HCC tissue. Compared with paired pericarcinous tissue, HCC tissue showed decreased PPM1a level. Besides, PPM1a level is negatively correlated with HBx expression. Taken together, our present study suggests that HBx-induced degradation of PPM1a is a novel mechanism for over-activation of TGF-β pathway in HCC development, which might provide potential candidates for clinical diagnosis and treatment.
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Affiliation(s)
- Yuan Liu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Yong Xu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Hongxin Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Bo Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Leiqi Xu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Hualin Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Xiaojia Song
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
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Meng Z, Zhang Y, Wei Z, Liu P, Kang J, Zhang Y, Ma D, Ke C, Chen Y, Luo J, Gong Z. High serum resistin associates with intrahepatic inflammation and necrosis: an index of disease severity for patients with chronic HBV infection. BMC Gastroenterol 2017; 17:6. [PMID: 28061755 PMCID: PMC5219659 DOI: 10.1186/s12876-016-0558-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 12/08/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Studies have revealed that resistin plays a role as an intrahepatic cytokine with proinflammatory activities. This study investigated the association between serum resistin and fibrosis severity and the possible marker role of resistin in the inflammatory process of chronic hepatitis B. METHODS In this study, 234 subjects with HBV infection were retrospectively selected, including 85 patients with chronic hepatitis B (CHB), 70 patients with HBV-related liver cirrhosis (LC-B), and 79 patients with HBV-related liver failure (LF-B). Serum levels of resistin, IL-1, IL-6, IL-17, IL-23, TNF-α, and TGF-β1 were assayed by ELISA. Demographic and clinical characteristics of patients were extracted from clinical databases of Taihe Hospital, Hubei University of Medicine, including serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), and liver stiffness (LS). RESULTS All the selected patients with HBV infection showed significantly increased levels of serum resistin, which was rarely detectable in the healthy controls. Serum resistin levels in patients with CHB, LC-B, and LF-B were 4.119 ± 5.848 ng/mL, 6.370 ± 6.834 ng/mL, and 6.512 ± 6.076 ng/mL, respectively. Compared with the CHB group, patients with LC-B or LF-B presented with significantly higher serum levels of resistin (p < 0.01). On the other hand, all of the enrolled patients had high serum levels of IL-1, IL-6, IL-17, TNF-α, and TGF-β1, but not IL-23. Interestingly, serum levels of resistin was significantly positively correlated with serum levels of TGF-β1 in LC-B patients (R = 0.3090, p = 0.0290), with IL-17 in LC-B (R = 0.4022, p = 0.0038) and LF-B patients (R = 0.5466, p < 0.0001), and with AST (R = 0.4501, p = 0.0036) and LS (R = 0.3415, p = 0.0310) in CHB patients. CONCLUSIONS High serum resistin associates with intrahepatic inflammation and necrosis and may be used as an index of disease severity for patients with chronic HBV infection.
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Affiliation(s)
- Zhongji Meng
- Department of Infectious Diseases, Hubei University of Medicine, Shiyan, China.,Institute of Biomedicine, Hubei University of Medicine, Shiyan, China
| | - Yonghong Zhang
- Institute of Wudang Chinese Medicine, Hubei University of Medicine, Shiyan, China
| | - Zhiqiang Wei
- Institute of Biomedicine, Hubei University of Medicine, Shiyan, China
| | - Ping Liu
- Department of Infectious Diseases, Hubei University of Medicine, Shiyan, China.,Department of Infectious Diseases, Renmin Hospital of Wuhan University, Zhangzhidong Road. 99, 430060, Wuhan, China
| | - Jian Kang
- Department of Infectious Diseases, Hubei University of Medicine, Shiyan, China
| | - Yinhua Zhang
- Department of Infectious Diseases, Hubei University of Medicine, Shiyan, China
| | - Deqiang Ma
- Department of Infectious Diseases, Hubei University of Medicine, Shiyan, China
| | - Changzheng Ke
- Department of Infectious Diseases, Hubei University of Medicine, Shiyan, China
| | - Yue Chen
- Department of Infectious Diseases, Hubei University of Medicine, Shiyan, China
| | - Jie Luo
- Department of Neurology, Taihe Hospital, Hubei University of Medicine, South Renmin Road. 32, 442000, Shiyan, Hubei, China.
| | - Zuojiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Zhangzhidong Road. 99, 430060, Wuhan, China.
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Debes JD, Bohjanen PR, Boonstra A. Mechanisms of Accelerated Liver Fibrosis Progression during HIV Infection. J Clin Transl Hepatol 2016; 4:328-335. [PMID: 28097102 PMCID: PMC5225153 DOI: 10.14218/jcth.2016.00034] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 10/14/2016] [Accepted: 10/21/2016] [Indexed: 12/23/2022] Open
Abstract
With the introduction of antiretroviral therapy (ART), a dramatic reduction in HIV-related morbidity and mortality has been observed. However, it is now becoming increasingly clear that liver-related complications, particularly rapid fibrosis development from ART as well as from the chronic HIV infection itself, are of serious concern to HIV patients. The pathophysiology of liver fibrosis in patients with HIV is a multifactorial process whereby persistent viral replication, and bacterial translocation lead to chronic immune activation and inflammation, which ART is unable to fully suppress, promoting production of fibrinogenic mediators and fibrosis. In addition, mitochondrial toxicity, triggered by both ART and HIV, contributes to intrahepatic damage, which is even more severe in patients co-infected with viral hepatitis. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV has been obtained, and these are detailed and discussed in this review.
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Affiliation(s)
- Jose D. Debes
- Department of Medicine, Division of Infectious Disease and International Medicine, University of Minnesota, Minneapolis, MN, USA
- *Correspondence to: Jose D. Debes, Department of Medicine, Division of Infectious Disease and International Medicine, University of Minnesota, 2001 6th Street SE, Minneapolis, MN 55455, USA. Tel: +1-612-624-6353, Fax: +1-612-301-1292, E-mail:
| | - Paul R. Bohjanen
- Department of Medicine, Division of Infectious Disease and International Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
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Interleukin-33 in the pathogenesis of liver fibrosis: alarming ILC2 and hepatic stellate cells. Cell Mol Immunol 2016; 14:143-145. [PMID: 28017959 DOI: 10.1038/cmi.2016.62] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Accepted: 10/23/2016] [Indexed: 02/06/2023] Open
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Di S, Ziyou Y, Liu NF. Pathological Changes of Lymphedematous Skin: Increased Mast Cells, Related Proteases, and Activated Transforming Growth Factor-β1. Lymphat Res Biol 2016; 14:162-71. [PMID: 27599355 DOI: 10.1089/lrb.2016.0010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Affiliation(s)
- Sun Di
- Department of Plastic and Reconstructive Surgery, Lymphology Centre, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Ziyou
- Department of Plastic and Reconstructive Surgery, Lymphology Centre, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ning-Fei Liu
- Department of Plastic and Reconstructive Surgery, Lymphology Centre, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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A deleterious role for Th9/IL-9 in hepatic fibrogenesis. Sci Rep 2016; 6:18694. [PMID: 26728971 PMCID: PMC4700496 DOI: 10.1038/srep18694] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 11/23/2015] [Indexed: 12/12/2022] Open
Abstract
T helper 9 (Th9) cells, a recently recognized Th cell subset, are involved in autoimmune diseases. We aimed to investigate the role of Th9/interleukin-9 (IL-9) in the pathogenesis of hepatic fibrosis. Th9 and Th17 cells were quantified in chronic hepatitis B (CHB) patients with hepatic fibrosis, HBV-associated liver cirrhosis (LC) patients and healthy controls (HC). The percentages of Th9 and Th17 cells, concentrations of IL-9 and IL-17, as well as expression of IL-17, TNF-α, IL-6, IL-4, IL-21, TGF-β1 and IFN-γ were significantly increased in plasma of CHB and LC patients compared with those in HC. Splenic Th9 and Th17 cells, plasma concentrations and liver expression of IL-9 and IL-17A were significantly elevated in mice with hepatic fibrosis compared with controls. Neutralization of IL-9 in mice ameliorated hepatic fibrosis, attenuated the activation of hepatic stellate cells, reduced frequencies of Th9, Th17 and Th1 cells in spleen, and suppressed expression of IL-9, IL-17A, IFN-γ, TGF-β1, IL-6, IL-4 and TNF-α in plasma and liver respectively. Our data suggest a deleterious role of Th9/IL-9 in increasing hepatic fibrosis and exacerbating disease endpoints, indicating that Th9/IL9 based immunotherapy may be a promising approach for treating hepatic fibrosis.
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