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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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Verhoeven F, Prati C, Di Martino V, Thevenot T, Demougeot C, Wendling D, Weil-Verhoeven D. Evolution of FIB-4 score in SpA and PsA patients taking anti-TNF or anti-IL17. Joint Bone Spine 2024; 91:105763. [PMID: 39084400 DOI: 10.1016/j.jbspin.2024.105763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/15/2024] [Accepted: 07/15/2024] [Indexed: 08/02/2024]
Affiliation(s)
- Frank Verhoeven
- Department of Rheumatology, CHRU of Besançon, Besançon, France; Université de Franche-Comté, EFS, Inserm, UMR RIGHT, 25000 Besançon, France.
| | - Clément Prati
- Department of Rheumatology, CHRU of Besançon, Besançon, France; Université de Franche-Comté, EFS, Inserm, UMR RIGHT, 25000 Besançon, France
| | - Vincent Di Martino
- Université de Franche-Comté, EFS, Inserm, UMR RIGHT, 25000 Besançon, France; Department of Hepatology, CHRU of Besançon, Besançon, France
| | - Thierry Thevenot
- Université de Franche-Comté, EFS, Inserm, UMR RIGHT, 25000 Besançon, France; Department of Hepatology, CHRU of Besançon, Besançon, France
| | - Céline Demougeot
- Université de Franche-Comté, EFS, Inserm, UMR RIGHT, 25000 Besançon, France
| | - Daniel Wendling
- Department of Rheumatology, CHRU of Besançon, Besançon, France; Université de Franche-Comté, EFS, Inserm, UMR RIGHT, 25000 Besançon, France
| | - Delphine Weil-Verhoeven
- Université de Franche-Comté, EFS, Inserm, UMR RIGHT, 25000 Besançon, France; Department of Hepatology, CHRU of Besançon, Besançon, France
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3
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Tang G, Nierath WF, Leitner E, Xie W, Revskij D, Seume N, Zhang X, Ehlers L, Vollmar B, Zechner D. Comparing animal well-being between bile duct ligation models. PLoS One 2024; 19:e0303786. [PMID: 38950046 PMCID: PMC11216573 DOI: 10.1371/journal.pone.0303786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 05/01/2024] [Indexed: 07/03/2024] Open
Abstract
A prevailing animal model currently used to study severe human diseases like obstructive cholestasis, primary biliary or sclerosing cholangitis, biliary atresia, and acute liver injury is the common bile duct ligation (cBDL). Modifications of this model include ligation of the left hepatic bile duct (pBDL) or ligation of the left bile duct with the corresponding left hepatic artery (pBDL+pAL). Both modifications induce cholestasis only in the left liver lobe. After induction of total or partial cholestasis in mice, the well-being of these animals was evaluated by assessing burrowing behavior, body weight, and a distress score. To compare the pathological features of these animal models, plasma levels of liver enzymes, bile acids, bilirubin, and within the liver tissue, necrosis, fibrosis, inflammation, as well as expression of genes involved in the synthesis or transport of bile acids were assessed. The survival rate of the animals and their well-being was comparable between pBDL+pAL and pBDL. However, surgical intervention by pBDL+pAL caused confluent necrosis and collagen depositions at the edge of necrotic tissue, whereas pBDL caused focal necrosis and fibrosis in between portal areas. Interestingly, pBDL animals had a higher survival rate and their well-being was significantly improved compared to cBDL animals. On day 14 after cBDL liver aspartate, as well as alanine aminotransferase, alkaline phosphatase, glutamate dehydrogenase, bile acids, and bilirubin were significantly elevated, but only glutamate dehydrogenase activity was increased after pBDL. Thus, pBDL may be primarily used to evaluate local features such as inflammation and fibrosis or regulation of genes involved in bile acid synthesis or transport but does not allow to study all systemic features of cholestasis. The pBDL model also has the advantage that fewer mice are needed, because of its high survival rate, and that the well-being of the animals is improved compared to the cBDL animal model.
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Affiliation(s)
- Guanglin Tang
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
- Department of General Surgery, Fushun Central Hospital, Fushun, Liaoning, China
| | - Wiebke-Felicitas Nierath
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Emily Leitner
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Wentao Xie
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Denis Revskij
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Nico Seume
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Xianbin Zhang
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
- Department of General Surgery & Institute of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy, Shenzhen, China
| | - Luise Ehlers
- Department of General Surgery, Fushun Central Hospital, Fushun, Liaoning, China
| | - Brigitte Vollmar
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Dietmar Zechner
- Rudolf-Zenker-Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
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Wang Y, Tan N, Su R, Liu Z, Hu N, Dong Q. Exploring the Potential Mechanisms of Action of Gentiana Veitchiorum Hemsl. Extract in the Treatment of Cholestasis using UPLC-MS/MS, Systematic Network Pharmacology, and Molecular Docking. Comb Chem High Throughput Screen 2024; 27:1948-1968. [PMID: 38357941 DOI: 10.2174/0113862073275657231210055250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 11/10/2023] [Accepted: 11/16/2023] [Indexed: 02/16/2024]
Abstract
INTRODUCTION Gentiana veitchiorum Hemsl. (GV) has a long history in Tibetan medicine for treating hepatobiliary disease cholestasis. However, the mechanisms mediating its efficacy in treating cholestasis have yet to be determined. AIM To elucidate the mechanisms of action of GV in the treatment of cholestasis, an integrated approach combining ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis with network pharmacology was established. MATERIALS AND METHODS A comprehensive analysis of the chemical composition of GV was achieved by UPLC-MS/MS. Subsequently, a network pharmacology method that integrated target prediction, a protein-protein interaction (PPI) network, gene set enrichment analysis, and a component- target-pathway network was established, and finally, molecular docking and experiments in vitro were conducted to verify the predicted results. RESULTS Twenty compounds that were extracted from GV were identified by UPLC-MS/MS analysis. Core proteins such as AKT1, TNF, and IL6 were obtained through screening in the Network pharmacology PPI network. The Kyoto Encyclopedia of the Genome (KEGG) pathway predicted that GV could treat cholestasis by acting on signaling pathways such as TNF/IL-17 / PI3K-Akt. Network pharmacology suggested that GV might exert a therapeutic effect on cholestasis by regulating the expression levels of inflammatory mediators, and the results were further confirmed by the subsequent construction of an LPS-induced RAW 264.7 cell model. CONCLUSIONS In this study, UPLC-MS/MS analysis, network pharmacology, and experiment validation were used to explore potential mechanisms of action of GV in the treatment of cholestasis.
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Affiliation(s)
- Yue Wang
- Medical College of Qinghai University, Xining, 810016, China
| | - Nixia Tan
- Medical College of Qinghai University, Xining, 810016, China
| | - Rong Su
- Medical College of Qinghai University, Xining, 810016, China
| | - Zhenhua Liu
- Medical College of Qinghai University, Xining, 810016, China
| | - Na Hu
- Qinghai Provincial Key Laboratory of Tibetan Medicine Research and CAS Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Qinghai, China
| | - Qi Dong
- Qinghai Provincial Key Laboratory of Tibetan Medicine Research and CAS Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Qinghai, China
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Nimphy J, Ibrahim S, Dayoub R, Kubitza M, Melter M, Weiss TS. Interleukin-1ß Attenuates Expression of Augmenter of Liver Regeneration (ALR) by Regulating HNF4α Independent of c-Jun. Int J Mol Sci 2023; 24:ijms24098107. [PMID: 37175814 PMCID: PMC10179097 DOI: 10.3390/ijms24098107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 04/28/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Inflammasomes and innate immune cells have been shown to contribute to liver injury, thereby activating Kupffer cells, which release several cytokines, including IL-6, IL-1ß, and TNFα. Augmenter of liver regeneration (ALR) is a hepatotropic co-mitogen that was found to have anti-oxidative and anti-apoptotic properties and to attenuate experimental non-alcoholic fatty liver disease (NAFLD) and cholestasis. Additionally, hepatic ALR expression is diminished in patients with NAFLD or cholestasis, but less is known about the mechanisms of its regulation under these conditions. Therefore, we aimed to investigate the role of IL-1ß in ALR expression and to elucidate the molecular mechanism of this regulation in vitro. We found that ALR promoter activity and mRNA and protein expression were reduced upon treatment with IL-1ß. Early growth response protein-1 (Egr-1), an ALR inducer, was induced by IL-1ß but could not activate ALR expression, which may be attributed to reduced Egr-1 binding to the ALR promoter. The expression and nuclear localization of hepatocyte nuclear factor 4 α (HNF4α), another ALR-inducing transcription factor, was reduced by IL-1ß. Interestingly, c-Jun, a potential regulator of ALR and HNF4α, showed increased nuclear phosphorylation levels upon IL-1ß treatment but did not change the expression of ALR or HNF4α. In conclusion, this study offers evidence regarding the regulation of anti-apoptotic and anti-oxidative ALR by IL-1ß through reduced Egr-1 promoter binding and diminished HNF4α expression independent of c-Jun activation. Low ALR tissue levels in NAFLD and cholestatic liver injury may be caused by IL-1ß and contribute to disease progression.
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Affiliation(s)
- Jonas Nimphy
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Sara Ibrahim
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Rania Dayoub
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Marion Kubitza
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Michael Melter
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Thomas S Weiss
- Children's University Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
- Center for Liver Cell Research, University Hospital Regensburg, 93053 Regensburg, Germany
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6
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Kong W, Li X, Zou M, Zhang Y, Cai H, Zhang L, Wang X. iNKT17 cells play a pathogenic role in ethinylestradiol-induced cholestatic hepatotoxicity. Arch Toxicol 2023; 97:561-580. [PMID: 36329302 DOI: 10.1007/s00204-022-03403-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022]
Abstract
IL-17 is closely associated with inflammation in intrahepatic cholestasis (IHC). Targeting IL-17 ameliorates IHC in mice. Invariant natural killer T (iNKT) cells are predominantly enriched in the liver and they mediate drug-induced liver injury through their secreted cytokines. However, whether iNKT17 cells are involved in ethinylestradiol (EE)-induced IHC remains unclear. In the present study, the administration of EE (10 mg/kg in vivo and 6.25 μM in vitro) promoted the activation and expansion of iNKT17 cells, which contributed to a novel hepatic iNKT17/Treg imbalance. iNKT cell-deficient Jα18-/- mice and the RORγt inhibitor digoxin (20 μg) alleviated EE-induced cholestatic hepatotoxicity and downregulated the IL-17 signalling pathway. In contrast, the co-administration of EE with recombinant IL-17 (1 μg) to Jα18-/- mice induced cholestatic hepatotoxicity and increased the infiltration of hepatic neutrophils and monocytes. Importantly, the administration of IL-17-/- iNKT cells (3.5 × 105) to Jα18-/- mice resulted in the attenuation of hepatotoxicity and the recruitment of fewer hepatic neutrophils and monocytes than the adoptive transfer of wild-type iNKT cells. These results indicated that iNKT17 cells could exert pathogenic effects. The recruitment and activation of iNKT17 cells could be attributed to the high level of CXCR3 expression on their surface. CXCL10 deficiency ameliorated EE-induced cholestatic liver damage, reduced hepatic CXCR3+ iNKT cells and inhibited RORγt expression. These findings suggest that iNKT17 cells play a key role in EE-induced cholestatic liver injury via CXCR3-mediated recruitment and activation. Our study provides new insights and therapeutic targets for cholestatic diseases.
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Affiliation(s)
- Weichao Kong
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Xinyu Li
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Mengzhi Zou
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Yiying Zhang
- Division of Biosciences, University College London, London, WC1E 6BT, UK
| | - Heng Cai
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Luyong Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Xinzhi Wang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
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Pinheiro D, Dias I, Freire T, Thole AA, Stumbo AC, Cortez EAC, de Carvalho L, de Carvalho SN. Effects of mesenchymal stem cells conditioned medium treatment in mice with cholestatic liver fibrosis. Life Sci 2021; 281:119768. [PMID: 34186042 DOI: 10.1016/j.lfs.2021.119768] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022]
Abstract
AIMS The purpose of this work was to study the effects of mesenchymal stem cells conditioned medium (MSC CM) treatment in animals with cholestatic liver fibrosis. MATERIALS AND METHODS We induced cholestatic liver fibrosis by bile duct ligation in C57Bl/6 mice. In the 5th and 6th days after bile duct ligation proceeding, conditioned medium obtained of cultures of mesenchymal stem cells derived from adipose tissue was injected in the animals. Blood levels of hepatic transaminases, alkaline phosphatase and albumin were measured in each group. Analysis of collagen deposition was realized by Picro Sirius red staining and cytokine profiling was performed by cytometric bead array (CBA). KEY FINDINGS Our results showed that MSC CM treatment decreased levels of hepatic enzymes and collagen deposition in the liver. After MSC CM treatment, profibrotic IL-17A was decreased andIL-6 and IL-4 were increased. SIGNIFICANCE In summary, MSC CM treatment demonstrated therapeutic potential to cholestatic liver fibrosis, favoring matrix remodeling and cytokine profile towards liver regeneration.
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Affiliation(s)
- Daphne Pinheiro
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute Roberto Alcântara Gomes, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil.
| | - Isabelle Dias
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute Roberto Alcântara Gomes, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil. http://lattes.cnpq.br/5186306427154406
| | - Thiago Freire
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute Roberto Alcântara Gomes, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil. http://lattes.cnpq.br/3641433792304902
| | - Alessandra Alves Thole
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute Roberto Alcântara Gomes, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil. http://lattes.cnpq.br/1579417282254465
| | - Ana Carolina Stumbo
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute Roberto Alcântara Gomes, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil. http://lattes.cnpq.br/0705651820739519
| | - Erika Afonso Costa Cortez
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute Roberto Alcântara Gomes, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil. http://lattes.cnpq.br/3564525125398107
| | - Lais de Carvalho
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute Roberto Alcântara Gomes, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil. http://lattes.cnpq.br/5375673766053793
| | - Simone Nunes de Carvalho
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute Roberto Alcântara Gomes, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil. http://lattes.cnpq.br/2268672866323829
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An SY, Petrescu AD, DeMorrow S. Targeting Certain Interleukins as Novel Treatment Options for Liver Fibrosis. Front Pharmacol 2021; 12:645703. [PMID: 33841164 PMCID: PMC8024568 DOI: 10.3389/fphar.2021.645703] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/16/2021] [Indexed: 12/14/2022] Open
Abstract
The liver is a major metabolic organ and an immunologically complex organ. It produces and uses many substances such as acute phase proteins, cytokines, chemokines, and complementary components to maintain the balance between immunity and tolerance. Interleukins are important immune control cytokines, that are produced by many body cells. In liver injury, interleukins are produced in large amount by various cell types, and act as pro-inflammatory (e.g. interleukin (IL)-6, IL-13, IL-17, and IL-33) as well as anti-inflammatory (e.g. IL-10) functions in hepatic cells. Recently, interleukins are regarded as interesting therapeutic targets for the treatment of liver fibrosis patients. Hepatic cells such as hepatocytes, hepatic stellate cells, and hepatic macrophages are involved to the initiation, perpetuation, and resolution of fibrosis. The understanding of the role of interleukins in such cells provides opportunity for the development of therapeutic target drugs. This paper aims to understand the functional roles of interleukins in hepatic and immune cells when the liver is damaged, and suggests the possibility of interleukins as a new treatment target in liver fibrosis.
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Affiliation(s)
- Su Yeon An
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, United States
| | - Anca D Petrescu
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, United States
| | - Sharon DeMorrow
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, United States.,Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, United States.,Research Division, Central Texas Veterans Healthcare System, Temple, TX, United States
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9
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Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature 2020; 587:555-566. [PMID: 33239795 DOI: 10.1038/s41586-020-2938-9] [Citation(s) in RCA: 1070] [Impact Index Per Article: 214.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 09/14/2020] [Indexed: 12/11/2022]
Abstract
Fibrosis can affect any organ and is responsible for up to 45% of all deaths in the industrialized world. It has long been thought to be relentlessly progressive and irreversible, but both preclinical models and clinical trials in various organ systems have shown that fibrosis is a highly dynamic process. This has clear implications for therapeutic interventions that are designed to capitalize on this inherent plasticity. However, despite substantial progress in our understanding of the pathobiology of fibrosis, a translational gap remains between the identification of putative antifibrotic targets and conversion of this knowledge into effective treatments in humans. Here we discuss the transformative experimental strategies that are being leveraged to dissect the key cellular and molecular mechanisms that regulate fibrosis, and the translational approaches that are enabling the emergence of precision medicine-based therapies for patients with fibrosis.
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Affiliation(s)
- Neil C Henderson
- University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK.,MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, USA.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Thomas A Wynn
- Inflammation & Immunology Research Unit, Pfizer Worldwide Research, Development & Medical, Cambridge, MA, USA.
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10
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Mai ZH, Huang Y, Huang D, Huang ZS, He ZX, Li PL, Zhang S, Weng JF, Gu WL. Reversine and herbal Xiang-Sha-Liu-Jun-Zi decoction ameliorate thioacetamide-induced hepatic injury by regulating the RelA/NF-κB/caspase signaling pathway. Open Life Sci 2020; 15:696-710. [PMID: 33817258 PMCID: PMC7747499 DOI: 10.1515/biol-2020-0059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/30/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
This study investigated the anti-fibrotic effects of reversine and Chinese medicine Xiang–Sha–Liu–Jun–Zi decoction (XSLJZD) on thioacetamide (TAA)-induced hepatic injury. Sprague-Dawley rats were intraperitoneally administered with TAA, then injected with reversine intraperitoneally, and/or orally provided with XSLJZD. TAA resulted in liver injury with increases in the liver index and levels of serum aspartate aminotransferase (AST) and alanine aminotransferase. Reversine alleviated the liver index and AST level and improved TAA-induced pathological changes but decreased TAA-induced collagen deposition, and α-smooth muscle actin and transforming growth factor-β1 expression. Reversine also modulated the mRNA levels of inflammatory cytokines, such as RelA, interleukin (IL)-17A, IL-22, IL-1β, IL-6, NLR family pyrin domain containing 3, platelet-derived growth factor, and monocyte chemoattractant protein, and suppressed nuclear factor (NF)-κB (p65) phosphorylation and caspase 1 activation. Meanwhile, XSLJZD protected TAA-injured liver without increasing fibrosis and enhanced the regulating effect of reversine on RelA, IL-17A, IL-1β, and MCP-1 cytokines. In conclusion, reversine ameliorates liver injury and inhibits inflammation reaction by regulating NF-κB, and XSLJZD protects the liver through its synergistic effect with reversine on regulating inflammatory cytokines.
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Affiliation(s)
- Zhen-Hao Mai
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Medical University, Guangzhou, Guangdong 510180, People's Republic of China
| | - Yu Huang
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, People's Republic of China
| | - Di Huang
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, People's Republic of China
| | - Zi-Sheng Huang
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Medical University, Guangzhou, Guangdong 510180, People's Republic of China
| | - Zhi-Xiang He
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China
| | - Pei-Lin Li
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China
| | - Shuai Zhang
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, People's Republic of China
| | - Jie-Feng Weng
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, People's Republic of China
| | - Wei-Li Gu
- Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 518180, People's Republic of China.,Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong 510180, People's Republic of China
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11
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Role of Interleukin-17 in Pathogenesis of Intestinal Fibrosis in Mice. Dig Dis Sci 2020; 65:1971-1979. [PMID: 31808003 DOI: 10.1007/s10620-019-05969-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 11/16/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The level of interleukin (IL)-17 is commonly increased in serum and intestinal mucosa of patients with inflammatory bowel disease, especially Crohn's disease with intestinal stricture. However, the role of IL-17 in the pathogenesis of intestinal fibrosis and the effect of anti-IL-17 treatment on intestinal fibrosis remain unclear; these issues are studied in vivo in this study. METHOD A total of 24 wild female Balb/c mice (18-22 g) were randomly divided into three groups: (1) control group, (2) 2,4,6-trinitrobenzenesulfonic acid (TNBS) + immunoglobulin G (IgG) group, and (3) TNBS + anti-IL-17 group. The levels of IL-17, IL-1β, transforming growth factor (TGF)-β1, and tumor necrosis factor (TNF)-α in blood and of collagen 3 and IL-17 in gut were measured by enzyme-linked immunosorbent assay (ELISA). The messenger RNA (mRNA) levels of collagen 3, IL-17, TNF-α, tissue inhibitor of metalloproteinase (TIMP)-1, and matrix metalloproteinase (MMP)-2 in gut were measured by reverse-transcription polymerase chain reaction. The protein expression of IL-17, collagen 3, TNF-α, TIMP-1, and MMP-2 were measured by immunoblot analysis. Collagen deposition was evaluated by standard hematoxylin and eosin and Masson's trichrome staining. RESULTS The profibrogenic cytokines IL-17, IL-1β, TGF-β1, and TNF-α in serum, mRNA levels of collagen 3, IL-17, TNF-α, TIMP-1, and MMP-2, and protein levels of IL-17, collagen 3, TNF-α, TIMP-1, and MMP-2 in gut were upregulated in TNBS-induced intestinal fibrosis mice. Treatment with anti-IL-17 antibody significantly alleviated intestinal fibrosis and reduced both mRNA and protein levels of collagen 3, TNF-α, TIMP-1, and MMP-2. The levels of profibrogenic cytokines IL-1β, TGF-β1, and TNF-α were also decreased in mice treated with anti-IL-17 antibody. CONCLUSIONS IL-17 contributes to the pathogenesis of intestinal fibrosis, and anti-IL-17 therapy may weaken this effect by downregulating expression of profibrogenic cytokines and disturbing the MMP/TIMPs balance.
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12
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Inflammation: Cause or consequence of chronic cholestatic liver injury. Food Chem Toxicol 2020; 137:111133. [PMID: 31972189 DOI: 10.1016/j.fct.2020.111133] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/04/2019] [Accepted: 01/14/2020] [Indexed: 12/12/2022]
Abstract
Cholestasis is a result of obstruction of the biliary tracts. It is a common cause of liver pathology after exposure to toxic xenobiotics and during numerous other liver diseases. Accumulation of bile acids in the liver is thought to be a major driver of liver injury during cholestasis and can lead to eventual liver fibrosis and cirrhosis. As such, current therapy in the field of chronic liver diseases with prominent cholestasis relies heavily on increasing choleresis to limit accumulation of bile acids. Many of these same diseases also present with autoimmunity before the onset of cholestasis though, indicating the inflammation may be an initiating component of the pathology. Moreover, cytotoxic inflammatory mediators accumulate during cholestasis and can propagate liver injury. Anti-inflammatory biologics and small molecules have largely failed clinical trials in these diseases though and as such, targeting inflammation as a means to address cholestatic liver injury remains debatable. The purpose of this review is to understand the different roles that inflammation can play during cholestatic liver injury and attempt to define how new therapeutic targets that limit or control inflammation may be beneficial for patients with chronic cholestatic liver disease.
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13
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Pinheiro D, Dias I, Ribeiro Silva K, Stumbo AC, Thole A, Cortez E, de Carvalho L, Weiskirchen R, Carvalho S. Mechanisms Underlying Cell Therapy in Liver Fibrosis: An Overview. Cells 2019; 8:cells8111339. [PMID: 31671842 PMCID: PMC6912561 DOI: 10.3390/cells8111339] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 12/19/2022] Open
Abstract
Fibrosis is a common feature in most pathogenetic processes in the liver, and usually results from a chronic insult that depletes the regenerative capacity of hepatocytes and activates multiple inflammatory pathways, recruiting resident and circulating immune cells, endothelial cells, non-parenchymal hepatic stellate cells, and fibroblasts, which become activated and lead to excessive extracellular matrix accumulation. The ongoing development of liver fibrosis results in a clinically silent and progressive loss of hepatocyte function, demanding the constant need for liver transplantation in clinical practice, and motivating the search for other treatments as the chances of obtaining compatible viable livers become scarcer. Although initially cell therapy has emerged as a plausible alternative to organ transplantation, many factors still challenge the establishment of this technique as a main or even additional therapeutic tool. Herein, the authors discuss the most recent advances and point out the corners and some controversies over several protocols and models that have shown promising results as potential candidates for cell therapy for liver fibrosis, presenting the respective mechanisms proposed for liver regeneration in each case.
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Affiliation(s)
- Daphne Pinheiro
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil.
| | - Isabelle Dias
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil.
| | - Karina Ribeiro Silva
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil.
| | - Ana Carolina Stumbo
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil.
| | - Alessandra Thole
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil.
| | - Erika Cortez
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil.
| | - Lais de Carvalho
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil.
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, D-52074 Aachen, Germany.
| | - Simone Carvalho
- Laboratory of Stem Cell Research, Histology and Embryology Department, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro 20550-170, Brazil.
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14
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Ramani K, Biswas PS. Interleukin-17: Friend or foe in organ fibrosis. Cytokine 2019; 120:282-288. [PMID: 30772195 DOI: 10.1016/j.cyto.2018.11.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 11/02/2018] [Accepted: 11/05/2018] [Indexed: 02/07/2023]
Abstract
Fibrosis affects all vital organs accounting for a staggering 45% of deaths worldwide and no effective therapies are currently available. Unresolved inflammation triggers downstream signaling events that lead to organ fibrosis. In recent years, proinflammatory cytokine Interleukin-17 (IL-17) has been implicated in several chronic inflammatory diseases that often culminate in organ damage followed by impaired wound healing and fibrosis. In this review, we outline the contribution of the IL-17 in mediating fibrotic diseases in various organs. A comprehensive understanding of the inflammatory events, and particularly the details of IL-17 signaling in vivo, could be beneficial in designing new therapeutic or preventive approaches to treat fibrosis. Additionally, understanding organ-specific differences in IL-17 activity could lead to targeted therapies and help spare other organs from unwanted side effects.
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Affiliation(s)
- Kritika Ramani
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Partha S Biswas
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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15
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Enyuan Q, Mingpeng X, Luoman G, Jinghua G, Yu L, Wentao L, Changchun H, Lihua L, Xiaoyan M, Lei Z, Guangnan L. Erythromycin combined with corticosteroid reduced inflammation and modified trauma-induced tracheal stenosis in a rabbit model. Ther Adv Respir Dis 2019; 12:1753466618773707. [PMID: 29781361 PMCID: PMC5966843 DOI: 10.1177/1753466618773707] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Background: Patients with endotracheal intubation or tracheostomy are subject to benign tracheal stenosis (TS), for which current therapies are unsatisfactory. We conducted a preliminary investigation of drugs and drug combinations for the prevention and treatment of TS in a rabbit model. Methods: Fifty-four rabbits were apportioned into nine groups according to treatment: sham-operated control; untreated TS model; amikacin; budesonide; erythromycin; penicillin; amikacin + budesonide; erythromycin + budesonide; and penicillin + budesonide. TS was induced by abrasion during surgery. The drugs were applied for 7 days before and 10 days after the surgery. Rabbits were killed on the eleventh day. Tracheal specimens were processed for determining alterations in the thicknesses of tracheal epithelium and lamina propria via hematoxylin and eosin. The tracheal mRNA (assessed by real-time quantitative polymerase chain reaction) expressions of the following fibrotic-related factors were determined: transforming growth factor-β1 (TGF- β1), collagen type I (COL1A1), collagen type III (COL3A1), and interleukin-17 (IL-17). The protein levels of TGF-β1, COL1A1, and COL3A1 were determined through immunohistochemistry and integrated optical densities. Results: Compared with all other groups, the untreated TS model had significantly thicker tracheal epithelium and lamina propria, and higher mRNA and protein levels of all targeted fibrotic factors. The mRNA and protein levels of the targeted fibrotic factors in all the drug-treated groups were lower than those of the untreated TS model, and differences were most significant in the erythromycin + budesonide group. Conclusions: Erythromycin combined with budesonide may reduce inflammation and modify fibrosis progression in TS after tracheal injury.
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Affiliation(s)
- Qin Enyuan
- Department of Respiratory Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xu Mingpeng
- Fourth People's Hospital of Nanning, Nanning, China
| | - Gan Luoman
- Department of Respiratory Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Gan Jinghua
- Department of Respiratory Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li Yu
- Department of Respiratory Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li Wentao
- Department of Respiratory Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hou Changchun
- Department of Respiratory Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li Lihua
- Department of Respiratory Medicine, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China
| | - Meng Xiaoyan
- Department of Respiratory Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhou Lei
- Department of Respiratory Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Liu Guangnan
- Department of Respiratory Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, China
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16
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Li H, Lee DJ. Epidemiology and Immunopathogenesis of Psoriasis and Its Comorbidities. CURRENT DERMATOLOGY REPORTS 2018. [DOI: 10.1007/s13671-018-0243-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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17
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Tu Z, Xiong J, Xiao R, Shao L, Yang X, Zhou L, Yuan W, Wang M, Yin Q, Wu Y, Pan S, Leng J, Jiang D, He C, Zhang Q. Loss of miR-146b-5p promotes T cell acute lymphoblastic leukemia migration and invasion via the IL-17A pathway. J Cell Biochem 2018; 120:5936-5948. [PMID: 30362152 DOI: 10.1002/jcb.27882] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 09/21/2018] [Indexed: 12/25/2022]
Abstract
Metastatic disease remains the primary cause of death for individuals with T cell acute lymphoblastic leukemia (T-ALL). microRNAs (miRNAs) play important roles in the pathogenesis of T-ALL by inhibiting gene expression at posttranscriptional levels. The goal of the current project is to identify any significant miRNAs in T-ALL metastasis. We observed miR-146b-5p to be downregulated in T-ALL patients and cell lines, and bioinformatics analysis implicated miR-146b-5p in the hematopoietic system. miR-146b-5p inhibited the migration and invasion in T-ALL cells. Interleukin-17A (IL-17A) was predicted to be a target of miR-146b-5p; this was confirmed by luciferase assays. Interestingly, T-ALL patients and cell lines secreted IL-17A and expressed the IL-17A receptor (IL-17RA). IL-17A/IL-17RA interactions promoted strong T-ALL cell migration and invasion responses. Gene set enrichment analysis (GSEA) and quantitative polymerase chain reaction (qPCR) analysis indicated that matrix metallopeptidase-9 (MMP9), was a potential downstream effector of IL-17A activation, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was also implicated in this process. Moreover, IL-17A activation promoted T-ALL cell metastasis to the liver in IL17A -/- mouse models. These results indicate that reduced miR-146b-5p expression in T-ALL may lead to the upregulation of IL-17A, which then promotes T-ALL cell migration and invasion by upregulating MMP9 via NF-κB signaling.
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Affiliation(s)
- Zhenbo Tu
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jie Xiong
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Ruijing Xiao
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Liang Shao
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xiangyong Yang
- Department of Bioengineering, Hubei University of Technology Engineering and Technology College, Wuhan, China
| | - Lu Zhou
- Department of Hematology, Taihe Hospital, Shiyan, China
| | - Wen Yuan
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Meng Wang
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Qian Yin
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Yingjie Wu
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Shan Pan
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jun Leng
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Daozi Jiang
- Department of Hematology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chunjiang He
- Department of Medical Genetics, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Qiuping Zhang
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China
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18
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Krueger JG, Brunner PM. Interleukin-17 alters the biology of many cell types involved in the genesis of psoriasis, systemic inflammation and associated comorbidities. Exp Dermatol 2017; 27:115-123. [PMID: 29152791 DOI: 10.1111/exd.13467] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2017] [Indexed: 02/06/2023]
Abstract
Psoriasis is a chronic, immune-mediated, systemic inflammatory disease that is defined by a characteristic skin reaction produced when elevated levels of inflammatory cytokines such as interleukin (IL)-17 alter the growth and differentiation of skin cells. The pathogenesis of comorbid conditions associated with psoriasis, including psoriatic arthritis, cardiovascular disease, obesity, metabolic syndrome, liver disorders, renal disease and depression, is also largely affected by inflammation. In this review, we examine the effect of IL-17 on the inflammatory pathways in a variety of different cell types, including keratinocytes, as well as epithelial cells of the colon, kidney, gut and liver. Additionally, we investigate the role of IL-17 in mediating the psoriasis-associated comorbidities detailed above.
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Affiliation(s)
- James G Krueger
- Laboratory of Investigative Dermatology, The Rockefeller University, New York, NY, USA
| | - Patrick M Brunner
- Laboratory of Investigative Dermatology, The Rockefeller University, New York, NY, USA
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19
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Cytokines, hepatic cell profiling and cell interactions during bone marrow cell therapy for liver fibrosis in cholestatic mice. PLoS One 2017; 12:e0187970. [PMID: 29176797 PMCID: PMC5703547 DOI: 10.1371/journal.pone.0187970] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 10/30/2017] [Indexed: 12/29/2022] Open
Abstract
Bone marrow cells (BMC) migrate to the injured liver after transplantation, contributing to regeneration through multiple pathways, but mechanisms involved are unclear. This work aimed to study BMC migration, characterize cytokine profile, cell populations and proliferation in mice with liver fibrosis transplanted with GFP+ BMC. Confocal microscopy analysis showed GFP+ BMC near regions expressing HGF and SDF-1 in the fibrotic liver. Impaired liver cell proliferation in fibrotic groups was restored after BMC transplantation. Regarding total cell populations, there was a significant reduction in CD68+ cells and increased Ly6G+ cells in transplanted fibrotic group. BMC contributed to the total populations of CD144, CD11b and Ly6G cells in the fibrotic liver, related to an increment of anti-fibrotic cytokines (IL-10, IL-13, IFN-γ and HGF) and reduction of pro-inflammatory cytokines (IL-17A and IL-6). Therefore, HGF and SDF-1 may represent important chemoattractants for transplanted BMC in the injured liver, where these cells can give rise to populations of extrahepatic macrophages, neutrophils and endothelial progenitor cells that can interact synergistically with other liver cells towards the modulation of an anti-fibrotic cytokine profile promoting the onset of liver regeneration.
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20
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Paquissi FC. Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis. Front Immunol 2017; 8:1195. [PMID: 29033929 PMCID: PMC5626935 DOI: 10.3389/fimmu.2017.01195] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 09/11/2017] [Indexed: 12/13/2022] Open
Abstract
Cirrhosis is a common final pathway for most chronic liver diseases; representing an increasing burden worldwide and is associated with increased morbidity and mortality. Current evidence has shown that, after an initial injury, the immune response has a significant participation in the ongoing damage, and progression from chronic viral hepatitis (CVH) to cirrhosis, driving the activation and maintenance of main fibrogenic pathways. Among immune deregulations, those related to the subtype 17 of T helper lymphocytes (Th17)/interleukin-17 (IL-17) axis have been recognized as key immunopathological and prognostic elements in patients with CVH. The Th17/IL-17 axis has been found involved in several points of fibrogenesis chain from the activation of stellate cells, increased expression of profibrotic factors as TGF-β, promotion of the myofibroblastic or epithelial–mesenchymal transition, stimulation of the synthesis of collagen, and induction of imbalance between matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). It also promotes the recruitment of inflammatory cells and increases the expression of proinflammatory cytokines such as IL-6 and IL-23. So, the Th17/IL-17 axis is simultaneously the fuel and the flame of a sustained proinflammatory and profibrotic environment. This work aims to present the immunopathologic and prognostic role of the Th17/IL-17 axis and related pathways in fibrogenesis and progression to cirrhosis in patients with liver disease due to hepatitis B virus (HBV) and hepatitis C virus (HCV).
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21
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Li M, Cai SY, Boyer JL. Mechanisms of bile acid mediated inflammation in the liver. Mol Aspects Med 2017; 56:45-53. [PMID: 28606651 DOI: 10.1016/j.mam.2017.06.001] [Citation(s) in RCA: 184] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 05/26/2017] [Accepted: 06/07/2017] [Indexed: 02/07/2023]
Abstract
Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.
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Affiliation(s)
- Man Li
- The Liver Center, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Shi-Ying Cai
- The Liver Center, Yale University School of Medicine, New Haven, CT 06510, USA
| | - James L Boyer
- The Liver Center, Yale University School of Medicine, New Haven, CT 06510, USA.
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22
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Chackelevicius CM, Gambaro SE, Tiribelli C, Rosso N. Th17 involvement in nonalcoholic fatty liver disease progression to non-alcoholic steatohepatitis. World J Gastroenterol 2016; 22:9096-9103. [PMID: 27895397 PMCID: PMC5107591 DOI: 10.3748/wjg.v22.i41.9096] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/22/2016] [Accepted: 09/14/2016] [Indexed: 02/06/2023] Open
Abstract
The nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a wide histological spectrum ranging from benign simple steatosis to non-alcoholic steatohepatitis (NASH). Sustained inflammation in the liver is critical in this process. Hepatic macrophages, including liver resident macropaghes (Kupffer cells), monocytes infiltrating the injured liver, as well as specific lymphocytes subsets play a pivotal role in the initiation and perpetuation of the inflammatory response, with a major deleterious impact on the progression of fatty liver to fibrosis. During the last years, Th17 cells have been involved in the development of inflammation not only in liver but also in other organs, such as adipose tissue or lung. Differentiation of a naïve T cell into a Th17 cell leads to pro-inflammatory cytokine and chemokine production with subsequent myeloid cell recruitment to the inflamed tissue. Th17 response can be mitigated by T regulatory cells that secrete anti-inflammatory cytokines. Both T cell subsets need TGF-β for their differentiation and a characteristic plasticity in their phenotype may render them new therapeutic targets. In this review, we discuss the role of the Th17 pathway in NAFLD progression to NASH and to liver fibrosis analyzing different animal models of liver injury and human studies.
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23
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Sato K, Hall C, Glaser S, Francis H, Meng F, Alpini G. Pathogenesis of Kupffer Cells in Cholestatic Liver Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:2238-47. [PMID: 27452297 DOI: 10.1016/j.ajpath.2016.06.003] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 05/18/2016] [Accepted: 06/07/2016] [Indexed: 02/08/2023]
Abstract
Kupffer cells are the resident macrophages in the liver. They are located in hepatic sinusoid, which allows them to remove foreign materials, pathogens, and apoptotic cells efficiently. Activated Kupffer cells secrete various mediators, including cytokines and chemokines, to initiate immune responses, inflammation, or recruitment of other liver cells. Bile duct ligation (BDL) surgery in rodents is often studied as an animal model of cholestatic liver disease, characterized by obstruction of bile flow. BDL mice show altered functional activities of Kupffer cells compared with sham-operated mice, including elevated cytokine secretion and impaired bacterial clearance. Various mediators produced by other liver cells can regulate Kupffer cell activation, which suggest that Kupffer cells orchestrate with other liver cells to relay inflammatory signals and to maintain liver homeostasis during BDL-induced liver injury. Blocking or depletion of Kupffer cells, an approach for the treatment of liver diseases, has shown controversial implications. Procedures in Kupffer cell research have limitations and may produce various results in Kupffer cell research. It is important, however, to reveal underlying mechanisms of activation and functions of Kupffer cells, followed by hepatic inflammation and fibrosis. This review summarizes present Kupffer cell studies in cholestatic liver injury.
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Affiliation(s)
- Keisaku Sato
- Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas
| | - Chad Hall
- Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Academic Research Integration, Department Surgery, Baylor Scott & White Healthcare, Temple, Texas
| | - Shannon Glaser
- Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas
| | - Heather Francis
- Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas
| | - Fanyin Meng
- Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas.
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