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Tang S, Wu S, Zhang W, Ma L, Zuo L, Wang H. Immunology and treatments of fatty liver disease. Arch Toxicol 2025; 99:127-152. [PMID: 39692857 DOI: 10.1007/s00204-024-03920-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 11/26/2024] [Indexed: 12/19/2024]
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are two major chronic liver diseases worldwide. The triggers for fatty liver can be derived from external sources such as adipose tissue, the gut, personal diet, and genetics, or internal sources, including immune cell responses, lipotoxicity, hepatocyte death, mitochondrial dysfunction, and extracellular vesicles. However, their pathogenesis varies to some extent. This review summarizes various immune mechanisms and therapeutic targets associated with these two types of fatty liver disease. It describes the gut-liver axis and adipose tissue-liver crosstalk, as well as the roles of different immune cells (both innate and adaptive immune cells) in fatty liver disease. Additionally, mitochondrial dysfunction, extracellular vesicles, microRNAs (miRNAs), and gastrointestinal hormones are also related to the pathogenesis of fatty liver. Understanding the pathogenesis of fatty liver and corresponding therapeutic strategies provides a new perspective for developing novel treatments for fatty liver disease.
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Affiliation(s)
- Sainan Tang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Shanshan Wu
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Wenzhe Zhang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Lili Ma
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China.
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China.
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2
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Xie G, Song Y, Li N, Zhang Z, Wang X, Liu Y, Jiao S, Wei M, Yu B, Wang Y, Wang H, Qu A. Myeloid peroxisome proliferator-activated receptor α deficiency accelerates liver regeneration via IL-6/STAT3 pathway after 2/3 partial hepatectomy in mice. Hepatobiliary Surg Nutr 2022; 11:199-211. [PMID: 35464270 DOI: 10.21037/hbsn-20-688] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 01/19/2021] [Indexed: 12/29/2022]
Abstract
Background Liver regeneration is a fundamental process for sustained body homeostasis and liver function recovery after injury. Emerging evidence demonstrates that myeloid cells play a critical role in liver regeneration by secreting cytokines and growth factors. Peroxisome proliferator-activated receptor α (PPARα), the target of clinical lipid-lowering fibrate drugs, regulates cell metabolism, proliferation, and survival. However, the role of myeloid PPARα in partial hepatectomy (PHx)-induced liver regeneration remains unknown. Methods Myeloid-specific PPARa-deficient (Ppara Mye-/-) mice and the littermate controls (Ppara fl/fl) were subjected to sham or 2/3 PHx to induce liver regeneration. Hepatocyte proliferation and mitosis were assessed by immunohistochemical (IHC) staining for 5-bromo-2'-deoxyuridine (BrdU) and Ki67 as well as hematoxylin and eosin (H&E) staining. Macrophage and neutrophil infiltration into livers were reflected by IHC staining for galectin-3 and myeloperoxidase (MPO) as well as flow cytometry analysis. Macrophage migration ability was evaluated by transwell assay. The mRNA levels for cell cycle or inflammation-related genes were measured by quantitative real-time RT-PCR (qPCR). The protein levels of cell proliferation related protein and phosphorylated signal transducer and activator of transcription 3 (STAT3) were detected by Western blotting. Results Ppara Mye-/- mice showed enhanced hepatocyte proliferation and mitosis at 32 h after PHx compared with Ppara fl/fl mice, which was consistent with increased proliferating cell nuclear antigen (Pcna) mRNA and cyclinD1 (CYCD1) protein levels in Ppara Mye-/- mice at 32 h after PHx, indicating an accelerated liver regeneration in Ppara Mye-/- mice. IHC staining showed that macrophages and neutrophils were increased in Ppara Mye-/- liver at 32 h after PHx. Livers of Ppara Mye-/- mice also showed an enhanced infiltration of M1 macrophages at 32 h after PHx. In vitro, Ppara-deficient bone marrow-derived macrophages (BMDMs) exhibited markedly enhanced migratory capacity and upregulated M1 genes Il6 and Tnfa but downregulated M2 gene Arg1 expressions. Furthermore, the phosphorylation of STAT3, a key transcript factor mediating IL6-promoted hepatocyte survival and proliferation, was reinforced in the liver of Ppara Mye-/- mice after PHx. Conclusions This study provides evidence that myeloid PPARα deficiency accelerates PHx-induced liver regeneration via macrophage polarization and consequent IL-6/STAT3 activation, thus providing a potential target for manipulating liver regeneration.
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Affiliation(s)
- Guomin Xie
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China
| | - Yanting Song
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China
| | - Na Li
- Department of Endocrinology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Zhenzhen Zhang
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Xia Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China
| | - Ye Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China
| | - Shiyu Jiao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China
| | - Ming Wei
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China
| | - Baoqi Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China
| | - Yan Wang
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China
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3
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Zhou K, Yin F, Li Y, Ma C, Liu P, Xin Z, Ren R, Wei S, Khan M, Wang H, Zhang H. MicroRNA-29b ameliorates hepatic inflammation via suppression of STAT3 in alcohol-associated liver disease. Alcohol 2022; 99:9-22. [PMID: 34688828 DOI: 10.1016/j.alcohol.2021.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 09/11/2021] [Accepted: 10/18/2021] [Indexed: 02/08/2023]
Abstract
Alcohol-associated liver disease (ALD) is induced by chronic excessive alcohol consumption resulting in the clinical manifestations of steatosis, inflammation, and cirrhosis. MicroRNA-29b (miR-29b) is mainly expressed in hepatic nonparenchymal cells, and its expression level varies in different diseases. In this study, we aimed to determine the role of miR-29b in a mouse model of alcohol-associated liver disease. Wild-type (WT) and miR-29b knockout (miR-29b-/-) mice were fed a Lieber-DeCarli liquid diet containing 5% alcohol for 10 days, followed by gavage of a single dose of ethanol (5 g/kg body weight). Histology, immunoblotting, and biochemical analyses were then conducted for comparison. miR-29b expression was decreased in the livers of chronic-plus-binge ethanol-fed mice. Further analysis revealed that alcohol exposure exacerbated hepatic injury by significantly increasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, with decreased survival rates for miR-29b-/- mice. Results from the luciferase assay indicated that miR-29b negatively regulated the signal transducer and activator of transcription 3 (STAT3). Depletion of miR-29b led to an increase in STAT3 and more noticeable inflammation in the liver, whereas overexpression of miR-29b downregulated STAT3 and proinflammatory cytokine expression in primary mouse peritoneal macrophages. Taken together, these results demonstrate a novel association between miR-29b and ALD. miR-29b plays a hepatoprotective role in alcohol-induced inflammation and liver injury by targeting STAT3.
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Brown CN, Atwood D, Pokhrel D, Holditch SJ, Altmann C, Skrypnyk NI, Bourne J, Klawitter J, Blaine J, Faubel S, Thorburn A, Edelstein CL. Surgical procedures suppress autophagic flux in the kidney. Cell Death Dis 2021; 12:248. [PMID: 33674554 PMCID: PMC7935862 DOI: 10.1038/s41419-021-03518-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 02/02/2021] [Accepted: 02/09/2021] [Indexed: 02/08/2023]
Abstract
Many surgical models are used to study kidney and other diseases in mice, yet the effects of the surgical procedure itself on the kidney and other tissues have not been elucidated. In the present study, we found that both sham surgery and unilateral nephrectomy (UNX), which is used as a model of renal compensatory hypertrophy, in mice resulted in increased mammalian target of rapamycin complex 1/2 (mTORC1/2) in the remaining kidney. mTORC1 is known to regulate lysosomal biogenesis and autophagy. Genes associated with lysosomal biogenesis and function were decreased in sham surgery and UNX kidneys. In both sham surgery and UNX, there was suppressed autophagic flux in the kidney as indicated by the lack of an increase in LC3-II or autophagosomes seen on immunoblot, IF and EM after bafilomycin A1 administration and a concomitant increase in p62, a marker of autophagic cargo. There was a massive increase in pro-inflammatory cytokines, which are known to activate ERK1/2, in the serum after sham surgery and UNX. There was a large increase in ERK1/2 in sham surgery and UNX kidneys, which was blocked by the MEK1/2 inhibitor, trametinib. Trametinib also resulted in a significant decrease in p62. In summary, there was an intense systemic inflammatory response, an ERK-mediated increase in p62 and suppressed autophagic flux in the kidney after sham surgery and UNX. It is important that researchers are aware that changes in systemic pro-inflammatory cytokines, ERK1/2 and autophagy can be caused by sham surgery as well as the kidney injury/disease itself.
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Affiliation(s)
- Carolyn N Brown
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO, USA
| | - Daniel Atwood
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO, USA
| | - Deepak Pokhrel
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO, USA
| | - Sara J Holditch
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO, USA
| | - Christopher Altmann
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO, USA
| | - Nataliya I Skrypnyk
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO, USA
| | - Jennifer Bourne
- Electron Microscopy Center, University of Colorado at Denver, Aurora, CO, USA
| | - Jelena Klawitter
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO, USA
- Department of Anesthesiology, University of Colorado at Denver, Aurora, CO, USA
| | - Judith Blaine
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO, USA
| | - Sarah Faubel
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO, USA
| | - Andrew Thorburn
- Department of Pharmacology, University of Colorado at Denver, Aurora, CO, USA
| | - Charles L Edelstein
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO, USA.
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Sehrawat TS, Liu M, Shah VH. The knowns and unknowns of treatment for alcoholic hepatitis. Lancet Gastroenterol Hepatol 2020; 5:494-506. [PMID: 32277902 DOI: 10.1016/s2468-1253(19)30326-7] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/26/2019] [Accepted: 08/29/2019] [Indexed: 02/06/2023]
Abstract
Alcoholic hepatitis is an acute, inflammatory liver disease associated with high morbidity and mortality both in the short term and long term. Alcoholic hepatitis often arises in patients with a background of chronic liver disease and it is characterised by the rapid onset of jaundice and the development of myriad complications. Medical therapy for severe alcoholic hepatitis relies on corticosteroids, which have modest effectiveness. Abstinence from alcohol is critically important in patients with alcoholic hepatitis, but recidivism is high. Because of the absence of effective medical treatments for alcoholic hepatitis and alcohol dependency, there is a pressing need to develop new and effective therapeutics. Supported by promising preliminary and preclinical studies, many ongoing clinical trials of new therapies for alcoholic hepatitis are currently underway and are discussed further in this Series paper.
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Affiliation(s)
- Tejasav S Sehrawat
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Mengfei Liu
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
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Lee JW, Beatty GL. Inflammatory networks cultivate cancer cell metastasis to the liver. Cell Cycle 2020; 19:642-651. [PMID: 32053029 PMCID: PMC7145328 DOI: 10.1080/15384101.2020.1728013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/28/2019] [Accepted: 02/06/2020] [Indexed: 02/08/2023] Open
Abstract
The liver is the most frequent site of metastatic spread in malignancies that arise from the digestive system, including pancreatic ductal adenocarcinoma (PDAC). Metastasis to the liver is a major cause of morbidity and mortality in cancer patients, yet mechanisms that govern this process remain poorly understood. Until recently, liver tropism of metastasis was believed to be driven by mechanical factors that direct the passive flow of circulating cancer cells to the liver. However, emerging evidence now shows that liver metastasis is a dynamic process that is, at least in part, dependent on the formation of a "pro-metastatic niche". Key features of this niche are myeloid cells and fibrosis that support cancer cell colonization and growth. Inflammatory responses that are mounted early during primary tumor development are critical for the recruitment of myeloid cells and the deposition of extracellular matrix (ECM) proteins within the liver. Intriguingly, the inflammatory processes that direct the formation of a pro-metastatic niche share remarkable resemblance to mechanisms of liver injury and regeneration, suggesting that cancer co-opts physiological liver functions to support metastasis. Therefore, therapeutic strategies that target key elements of liver inflammation that form the basis of a pro-metastatic niche may lead to effective treatments for metastatic cancer.
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Affiliation(s)
- Jae W. Lee
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Gregory L. Beatty
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Participation of 5-lipoxygenase and LTB4 in liver regeneration after partial hepatectomy. Sci Rep 2019; 9:18176. [PMID: 31796842 PMCID: PMC6890767 DOI: 10.1038/s41598-019-54652-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 11/18/2019] [Indexed: 12/12/2022] Open
Abstract
Regeneration is the unmatched liver ability for recovering its functional mass after tissue lost. Leukotrienes (LT) are a family of eicosanoids with the capacity of signaling to promote proliferation. We analyzed the impact of blocking LT synthesis during liver regeneration after partial hepatectomy (PH). Male Wistar rats were subjected to two-third PH and treated with zileuton, a specific inhibitor of 5-lipoxygenase (5-LOX). Our first find was a significant increment of intrahepatic LTB4 during the first hour after PH together with an increase in 5-LOX expression. Zileuton reduced hepatic LTB4 levels at the moment of hepatectomy and also inhibited the increase in hepatic LTB4. This inhibition produced a delay in liver proliferation as seen by decreased PCNA and cyclin D1 nuclear expression 24 h post-PH. Results also showed that hepatic LTB4 diminution by zileuton was associated with a decrease in NF-ĸB activity. Additionally, decreased hepatic LTB4 levels by zileuton affected the recruitment of neutrophils and macrophages. Non-parenchymal cells (NPCs) from zileuton-treated PH-rats displayed higher apoptosis than NPCs from PH control rats. In conclusion, the present work provides evidences that 5-LOX activation and its product LTB4 are involved in the initial signaling events for liver regeneration after PH and the pharmacological inhibition of this enzyme can delay the initial time course of the phenomenon.
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8
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Bhattacharjee S, Mejías-Luque R, Loffredo-Verde E, Toska A, Flossdorf M, Gerhard M, Prazeres da Costa C. Concomitant Infection of S. mansoni and H. pylori Promotes Promiscuity of Antigen-Experienced Cells and Primes the Liver for a Lower Fibrotic Response. Cell Rep 2019; 28:231-244.e5. [DOI: 10.1016/j.celrep.2019.05.108] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 01/29/2019] [Accepted: 05/29/2019] [Indexed: 12/12/2022] Open
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9
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Hata T, Rehman F, Hori T, Nguyen JH. GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury. J Surg Res 2019; 236:172-183. [PMID: 30694753 PMCID: PMC6420924 DOI: 10.1016/j.jss.2018.11.047] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 11/01/2018] [Accepted: 11/21/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Acute liver failure (ALF) from severe acute liver injury is a critical condition associated with high mortality. The purpose of this study was to investigate the impact of preemptive administration of γ-aminobutyric acid (GABA) on hepatic injury and survival outcomes in mice with experimentally induced ALF. MATERIALS AND METHODS To induce ALF, C57BL/6NHsd mice were administered GABA, saline, or nothing for 7 d, followed by intraperitoneal administration of 500 μg of tumor necrosis factor α and 20 mg of D-galactosamine. The study mice were humanely euthanized 4-5 h after ALF was induced or observed for survival. Proteins present in the blood samples and liver tissue from the euthanized mice were analyzed using Western blot and immunohistochemical and histopathologic analyses. For inhibition studies, we administered the STAT3-specific inhibitor, NSC74859, 90 min before ALF induction. RESULTS We found that GABA-treated mice had substantial attenuation of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive hepatocytes and hepatocellular necrosis, decreased caspase-3, H2AX, and p38 MAPK protein levels and increased expressions of Jak2, STAT3, Bcl-2, and Mn-SOD, with improved mitochondrial integrity. The reduced apoptotic proteins led to a significantly prolonged survival after ALF induction in GABA-treated mice. The STAT3-specific inhibitor NSC74859 eliminated the survival advantage in GABA-treated mice with ALF, indicating the involvement of the STAT3 pathway in GABA-induced reduction in apoptosis. CONCLUSIONS Our results showed that preemptive treatment with GABA protected against severe acute liver injury in mice via GABA-mediated STAT3 signaling. Preemptive administration of GABA may be a useful approach to optimize marginal donor livers before transplantation.
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Affiliation(s)
- Toshiyuki Hata
- Department of Hepatobiliary-pancreatic and Transplant Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Fatima Rehman
- Department of Biology, University of North Florida, Jacksonville, Florida
| | - Tomohide Hori
- Department of Hepatobiliary-pancreatic and Transplant Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Justin H Nguyen
- Division of Transplant Surgery, Mayo Clinic, Jacksonville, Florida.
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10
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Li Y, Shen Y, Lin D, Zhang H, Wang T, Liu H, Wang Y. Neutrophils and IL17A mediate flagellar hook protein FlgE-induced mouse acute lung inflammation. Cell Microbiol 2018; 21:e12975. [PMID: 30412932 DOI: 10.1111/cmi.12975] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 10/30/2018] [Accepted: 10/31/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Yuanyuan Li
- MOH Key Lab of Thrombosis and Hemostasis, Collaborative Innovation Center of Hematology-Thrombosis and Hemostasis Group, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, College of Medicine; Soochow University; Suzhou China
| | - Ying Shen
- MOH Key Lab of Thrombosis and Hemostasis, Collaborative Innovation Center of Hematology-Thrombosis and Hemostasis Group, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, College of Medicine; Soochow University; Suzhou China
| | - Dandan Lin
- MOH Key Lab of Thrombosis and Hemostasis, Collaborative Innovation Center of Hematology-Thrombosis and Hemostasis Group, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, College of Medicine; Soochow University; Suzhou China
| | - Hongbo Zhang
- Department of Clinical Laboratory; Qilu Hospital of Shandong University (Qingdao); Qingdao China
| | - Ting Wang
- MOH Key Lab of Thrombosis and Hemostasis, Collaborative Innovation Center of Hematology-Thrombosis and Hemostasis Group, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, College of Medicine; Soochow University; Suzhou China
| | - Haiyan Liu
- Immunology Programme, Life Sciences Institute and Department of Microbiology; National University of Singapore; Singapore Singapore
| | - Yiqiang Wang
- MOH Key Lab of Thrombosis and Hemostasis, Collaborative Innovation Center of Hematology-Thrombosis and Hemostasis Group, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, College of Medicine; Soochow University; Suzhou China
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11
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Xie G, Yin S, Zhang Z, Qi D, Wang X, Kim D, Yagai T, Brocker CN, Wang Y, Gonzalez FJ, Wang H, Qu A. Hepatocyte Peroxisome Proliferator-Activated Receptor α Enhances Liver Regeneration after Partial Hepatectomy in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 189:272-282. [PMID: 30448405 DOI: 10.1016/j.ajpath.2018.10.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 09/18/2018] [Accepted: 10/10/2018] [Indexed: 12/25/2022]
Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a key nuclear receptor involved in the control of lipid homeostasis. In rodents, PPARα is also a potent hepatic mitogen. Hepatocyte-specific disruption of PPARα inhibits agonist-induced hepatocyte proliferation; however, little is known about the exact role of PPARα in partial hepatectomy (PHx)-induced liver regeneration. Herein, using hepatocyte-specific PPARα-deficient (PparaΔHep) mice, the function of hepatocyte PPARα in PHx-induced liver regeneration was investigated. PPARα protein level and transcriptional activity were increased in the liver after PHx. Compared with the Pparafl/fl mice, PparaΔHep mice exhibited significantly reduced hepatocyte proliferation at 32 hours after PHx. Consistently, reduced Ccnd1 and Pcna mRNA and CYCD1 and proliferating cell nuclear antigen protein were observed at 32 hours after PHx in PparaΔHep mice. Furthermore, PparaΔHep mice showed increased hepatic lipid accumulation and enhanced hepatic triglyceride contents because of impaired hepatic fatty acid β-oxidation when compared with that observed in Pparafl/fl mice. These results indicate that PPARα promotes liver regeneration after PHx, at least partially via regulating the cell cycle and lipid metabolism.
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Affiliation(s)
- Guomin Xie
- School of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Capital Medical University, Beijing, China
| | - Shi Yin
- Department of Geriatrics, Anhui Provincial Hospital, Anhui Medical University, Hefei, China
| | - Zhenzhen Zhang
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Dan Qi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Capital Medical University, Beijing, China
| | - Xia Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Capital Medical University, Beijing, China
| | - Donghwan Kim
- Laboratory of Metabolism, National Cancer Institute, NIH, Bethesda, Maryland
| | - Tomoki Yagai
- Laboratory of Metabolism, National Cancer Institute, NIH, Bethesda, Maryland
| | - Chad N Brocker
- Laboratory of Metabolism, National Cancer Institute, NIH, Bethesda, Maryland
| | - Yan Wang
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, NIH, Bethesda, Maryland
| | - Hua Wang
- School of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, China; Department of Oncology, First Affiliated Hospital, Anhui Medical University, Hefei, China; Institute for Liver Diseases, Anhui Medical University, Hefei, China.
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Capital Medical University, Beijing, China.
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12
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Zhou H, Xie G, Mao Y, Zhou K, Ren R, Zhao Q, Wang H, Yin S. Enhanced Regeneration and Hepatoprotective Effects of Interleukin 22 Fusion Protein on a Predamaged Liver Undergoing Partial Hepatectomy. J Immunol Res 2018; 2018:5241526. [PMID: 30515423 PMCID: PMC6234454 DOI: 10.1155/2018/5241526] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/29/2018] [Indexed: 02/06/2023] Open
Abstract
Liver ischemia-reperfusion injury (IRI) and regeneration deficiency are two major challenges for surgery patients with chronic liver disease. As a survival factor for hepatocytes, interleukin 22 (IL-22) plays an important role in hepatoprotection and the promotion of regeneration after hepatectomy. In this study, we aim to investigate the roles of an interleukin 22 fusion protein (IL-22-FP) in mice with a predamaged liver after a two-third partial hepatectomy (PHx). Predamaged livers in mice were induced by concanavalin A (ConA)/carbon tetrachloride (CCl4) following PHx with or without IL-22-FP treatment. A hepatic IRI mouse model was also used to determine the hepatoprotective effects of IL-22-FP. In the ConA/CCl4 model, IL-22-FP treatment alleviated liver injury and accelerated hepatocyte proliferation. Administration of IL-22-FP activated the hepatic signal transducer and activator of transcription 3 (STAT3) and upregulated the expression of many mitogenic proteins. IL-22-FP treatment prior to IRI effectively reduced liver damage through decreased aminotransferase and improved liver histology. In conclusion, IL-22-FP promotes liver regeneration in mice with predamaged livers following PHx and alleviates IRI-induced liver injury. Our study suggests that IL-22-FP may represent a promising therapeutic drug against regeneration deficiency and liver IRI in patients who have undergone PHx.
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Affiliation(s)
- Heng Zhou
- Department of Geriatrics, Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, China
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Institute for Liver Disease, Anhui Medical University, Hefei 230032, China
| | - Guomin Xie
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Institute for Liver Disease, Anhui Medical University, Hefei 230032, China
| | - Yudi Mao
- Department of Geriatrics, Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, China
| | - Ke Zhou
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Institute for Liver Disease, Anhui Medical University, Hefei 230032, China
| | - Ruixue Ren
- Institute for Liver Disease, Anhui Medical University, Hefei 230032, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Qihong Zhao
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Hua Wang
- Institute for Liver Disease, Anhui Medical University, Hefei 230032, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Shi Yin
- Department of Geriatrics, Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, China
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13
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Abe M, Yoshida T, Akiba J, Ikezono Y, Wada F, Masuda A, Sakaue T, Tanaka T, Iwamoto H, Nakamura T, Sata M, Koga H, Yoshimura A, Torimura T. STAT3 deficiency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury. World J Gastroenterol 2017; 23:6833-6844. [PMID: 29085226 PMCID: PMC5645616 DOI: 10.3748/wjg.v23.i37.6833] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 08/24/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury.
METHODS We investigated thioacetamide (TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma (HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAA-induced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9 (SOX9) and Yes-associated protein (YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.
RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.
CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.
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Affiliation(s)
- Mitsuhiko Abe
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Takafumi Yoshida
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
- Kurume Clinical Pharmacology Clinic, Kurume 830-0011, Japan
| | - Jun Akiba
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume 830-0011, Japan
| | - Yu Ikezono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Fumitaka Wada
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Atsutaka Masuda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Takahiko Sakaue
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Toshimitsu Tanaka
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Toru Nakamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Michio Sata
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
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14
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Li Y, Wang S, Fan J, Zhang X, Qian X, Zhang X, Luan J, Song P, Wang Z, Chen Q, Ju D. Targeting TNFα Ameliorated Cationic PAMAM Dendrimer-Induced Hepatotoxicity via Regulating NLRP3 Inflammasomes Pathway. ACS Biomater Sci Eng 2017; 3:843-853. [DOI: 10.1021/acsbiomaterials.6b00790] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Yubin Li
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
- Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced
Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Shaofei Wang
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
- Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced
Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Jiajun Fan
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
- Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced
Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Xuesai Zhang
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
- Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced
Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Xiaolu Qian
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
- Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced
Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Xuyao Zhang
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
- Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced
Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Jingyun Luan
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
- Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced
Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Ping Song
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
- Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced
Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Ziyu Wang
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
- Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced
Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Qicheng Chen
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
- Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced
Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Dianwen Ju
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, and §Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
- Department of Dermatology, Perelman School of Medicine, and ∥Center for Advanced
Rentinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
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15
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Bergmann J, Müller M, Baumann N, Reichert M, Heneweer C, Bolik J, Lücke K, Gruber S, Carambia A, Boretius S, Leuschner I, Becker T, Rabe B, Herkel J, Wunderlich FT, Mittrücker HW, Rose-John S, Schmidt-Arras D. IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology 2017; 65:89-103. [PMID: 27770462 DOI: 10.1002/hep.28874] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 09/08/2016] [Accepted: 09/11/2016] [Indexed: 12/11/2022]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin-6 (IL-6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL-6 classic and the IL-6 trans-signaling pathway. Whereas IL-6 classic signaling is important for innate and acquired immunity, IL-6 trans-signaling has been linked to accelerated liver regeneration and several chronic inflammatory pathologies. However, its implication in liver tumorigenesis has not been addressed yet. Here, we show that IL-6 trans-signaling, but not IL-6 classic signaling, is essential to promote hepatocellular carcinogenesis by two mechanisms: First, it prevents DNA-damage-induced hepatocyte apoptosis through suppression of p53 and enhances β-catenin activation and tumor proliferation. Second, IL-6 trans-signaling directly induces endothelial cell proliferation to promote tumor angiogenesis. Consequently, soluble gp130 fused to Fc transgenic mice lacking IL-6 trans-signaling are largely protected from tumor formation in a diethylnitrosamine/3,3',5,5'-tetrachloro-1,4-bis(pyridyloxy)benzene model of HCC. CONCLUSION IL-6 trans-signaling, and not IL-6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL-6 classic signaling-driven protective immune responses. (Hepatology 2017;65:89-103).
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Affiliation(s)
- Juri Bergmann
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.,Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Miryam Müller
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Niklas Baumann
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Manuel Reichert
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.,Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Carola Heneweer
- Department of Radiology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Julia Bolik
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Karsten Lücke
- Institute of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Sabine Gruber
- Max-Planck-Institute for Metabolism Research, CECAD and Institute for Genetics, Cologne, Germany
| | - Antonella Carambia
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Susanne Boretius
- Department of Radiology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Ivo Leuschner
- Institute of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Thomas Becker
- Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Björn Rabe
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Johannes Herkel
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - F Thomas Wunderlich
- Max-Planck-Institute for Metabolism Research, CECAD and Institute for Genetics, Cologne, Germany
| | - Hans-Willi Mittrücker
- Institute of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Dirk Schmidt-Arras
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany
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16
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Abstract
Alcoholic liver disease (ALD) is a complex process that includes a wide spectrum of hepatic lesions, from steatosis to cirrhosis. Cell injury, inflammation, oxidative stress, regeneration and bacterial translocation are key drivers of alcohol-induced liver injury. Alcoholic hepatitis is the most severe form of all the alcohol-induced liver lesions. Animal models of ALD mainly involve mild liver damage (that is, steatosis and moderate inflammation), whereas severe alcoholic hepatitis in humans occurs in the setting of cirrhosis and is associated with severe liver failure. For this reason, translational studies using humans and human samples are crucial for the development of new therapeutic strategies. Although multiple attempts have been made to improve patient outcome, the treatment of alcoholic hepatitis is still based on abstinence from alcohol and brief exposure to corticosteroids. However, nearly 40% of patients with the most severe forms of alcoholic hepatitis will not benefit from treatment. We suggest that future clinical trials need to focus on end points other than mortality. This Review discusses the main pathways associated with the progression of liver disease, as well as potential therapeutic strategies targeting these pathways.
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17
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Yin S, Wang H, Bertola A, Feng D, Xu MJ, Wang Y, Gao B. Activation of invariant natural killer T cells impedes liver regeneration by way of both IFN-γ- and IL-4-dependent mechanisms. Hepatology 2014; 60:1356-66. [PMID: 24623351 PMCID: PMC4190674 DOI: 10.1002/hep.27128] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 03/10/2014] [Indexed: 12/18/2022]
Abstract
UNLABELLED Invariant natural killer T (iNKT) cells are a major subset of lymphocytes found in the liver. These cells mediate various functions, including hepatic injury, fibrogenesis, and carcinogenesis. However, the function of iNKT cells in liver regeneration remains unclear. In the present study, partial hepatectomy (PHx) was used to study liver regeneration. α-Galactosylceramide (α-GalCer), a specific ligand for iNKT cells, was used to induce iNKT cell activation. After PHx, two strains of iNKT cell-deficient mice, CD1d(-/-) and Jα281(-/-) mice, showed normal liver regeneration. Injection of α-GalCer before or after PHx, which rapidly stimulated interferon-gamma (IFN-γ) and interleukin (IL)-4 production by iNKT cells, markedly inhibited liver regeneration. In vitro treatment with IFN-γ inhibited hepatocyte proliferation. In agreement with this in vitro finding, genetic disruption of IFN-γ or its downstream signaling molecule signal transducer and activator of transcription (STAT)1 significantly abolished the α-GalCer-mediated inhibition of liver regeneration. In vitro exposure to IL-4 did not affect hepatocyte proliferation, but surprisingly, genetic ablation of IL-4 or its downstream signaling molecule STAT6 partially eliminated the inhibitory effect of α-GalCer on liver regeneration. Further studies revealed that IL-4 contributed to α-GalCer-induced iNKT cell expansion and IFN-γ production, thereby inhibiting liver regeneration. CONCLUSION iNKT cells play a minor role in controlling liver regeneration after PHx under healthy conditions. Activation of iNKT cells by α-GalCer induces the production of IFN-γ, which directly inhibits liver regeneration, and IL-4, which indirectly attenuates liver regeneration by stimulating iNKT cell expansion and IFN-γ production.
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Affiliation(s)
- Shi Yin
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
- Department of Geriatrics, Affiliated Provincial Hospitalof Anhui Medical University
| | - Hua Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
- Institute for Liver Diseases, Anhui Medical University, Hefei, 230032, China
| | - Adeline Bertola
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ming-jiang Xu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yan Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
- Corresponding author: Bin Gao, M.D., Ph.D., Laboratory of Liver Diseases, NIAAA/NIH, 5625 Fishers Lane, Bethesda, MD 20892., Tel: 301-443-3998;
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18
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Xu J, Liu X, Gao B, Karin M, Tsukamoto H, Brenner D, Kisseleva T. New Approaches for Studying Alcoholic Liver Disease. CURRENT PATHOBIOLOGY REPORTS 2014; 2:171-183. [PMID: 26594598 DOI: 10.1007/s40139-014-0053-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) is major cause of chronic liver injury which results in liver fibrosis and cirrhosis. According to the surveillance report published by the National Institute on Alcohol Abuse and Alcoholism, liver cirrhosis is the 12th leading cause of death in the United States with 48 % of these deaths being attributed to excessive alcohol consumption. ALD includes a spectrum of disorders from simple steatosis to steatohepatitis, fibrosis, and hepatocellular carcinoma. Several mechanisms play a critical role in the pathogenesis of ALD. These include ethanol-induced oxidative stress and depletion of glutathione, pathological methionine metabolism, increased gut permeability and release of endotoxins into the portal blood, recruitment and activation of inflammatory cells including bone marrow-derived and liver resident macrophages (Kupffer cells). Chronic alcohol consumption results in liver damage and activation of hepatic stellate cells (HSCs) and myofibroblasts, leading to liver fibrosis. Here we discuss the current view on factors that are specific for different stages of ALD and those that regulate its progression, including cytokines and chemokines, alcohol-responsive intracellular signaling pathways, and transcriptional factors. We also review recent studies demonstrating that alcohol-mediated changes can be regulated on an epigenetic level, including microRNAs. Finally, we discuss the reversibility of liver fibrosis and inactivation of HSCs as a potential strategy for treating alcohol-induced liver damage.
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Affiliation(s)
- Jun Xu
- Department of Medicine, UC San Diego, San Diego, CA, USA
| | - Xiao Liu
- Department of Medicine, UC San Diego, San Diego, CA, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Michael Karin
- Department of Pharmacology, UC San Diego, San Diego, CA, USA
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD & Cirrhosis Department of Pathology Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA
| | - David Brenner
- Department of Medicine, UC San Diego, San Diego, CA, USA
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Svinka J, Mikulits W, Eferl R. STAT3 in hepatocellular carcinoma: new perspectives. Hepat Oncol 2014; 1:107-120. [PMID: 30190945 PMCID: PMC6114013 DOI: 10.2217/hep.13.7] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Chronic liver damage and inflammation are strong promoters of hepatocellular carcinoma (HCC) formation. HCC cells communicate with inflammatory and stromal cells via cytokine/chemokine signals. These heterotypic interactions inhibit immunologic anticancer activities and promote protumorigenic activities, such as angiogenesis or invasiveness. STAT3 mediates several reciprocal interactions between liver cancer cells and stromal cells and modulates preconditions of tumor formation such as chronic inflammation. Therefore, activation of STAT3 is considered as a tumor-promoting event in HCC formation. However, the oncogenic role of STAT3 in cancers has been challenged by several reports that suggest a tumor-suppressive activity. Here we discuss tumor-promoting and tumor-suppressive effects of cytokine-activated STAT3 in HCC.
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Affiliation(s)
- Jasmin Svinka
- Medical University Vienna & Comprehensive Cancer Center, Institute for Cancer Research, Borschkegasse 8a, A-1090 Vienna, Austria
| | - Wolfgang Mikulits
- Medical University Vienna & Comprehensive Cancer Center, Institute for Cancer Research, Borschkegasse 8a, A-1090 Vienna, Austria
| | - Robert Eferl
- Medical University Vienna & Comprehensive Cancer Center, Institute for Cancer Research, Borschkegasse 8a, A-1090 Vienna, Austria
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20
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Kuklin A, Tokovenko B, Makogon N, Oczko-Wojciechowska M, Jarząb B, Obolenskaya M. Hepatocytes response to interferon alpha levels recorded after liver resection. J Interferon Cytokine Res 2013; 34:90-9. [PMID: 24107099 DOI: 10.1089/jir.2012.0125] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Extensive damage of liver parenchyma stimulates hepatic cells to transit from quiescence to proliferation with eventual restoration of liver mass and function. Our recent studies have revealed upregulated expression of interferon (IFN)-α and its antiviral activity during the early hours after partial hepatectomy. In this study, we analyzed the response of primary hepatocytes from intact liver to IFN-α mimicking its levels (250 U/mL) during the transition period of liver restoration. The gene expression profile was analyzed with rat genome array 230 2.0 (Affymetrix). After 3- and 6-h treatment we identified respectively 28 and 124 differentially expressed genes responsible for autonomous changes in hepatocytes and those involving non-parenchymal cells in a concerted response to IFN-α. The response has an energy sparing character and affects all levels of gene expression. The factors activating T cells and apoptosis are opposed by those restricting the signal propagation, inhibiting T cells activation, and promoting survival. The partial resemblance between the specific in vitro response to IFN-α and the processes in regenerating liver is discussed. Our study opens the way to a more focused investigation of the liver cell response to quasiphysiological dose of IFN-α.
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Affiliation(s)
- Andrii Kuklin
- 1 Institute of Molecular Biology and Genetics , National Academy of Sciences of Ukraine, Kyiv, Ukraine
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21
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Lv K, Zhang Y, Zhang M, Zhong M, Suo Q. Galectin-9 ameliorates Con A-induced hepatitis by inducing CD4(+)CD25(low/int) effector T-Cell apoptosis and increasing regulatory T cell number. PLoS One 2012; 7:e48379. [PMID: 23118999 PMCID: PMC3485226 DOI: 10.1371/journal.pone.0048379] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Accepted: 09/24/2012] [Indexed: 02/07/2023] Open
Abstract
Background T cell-mediated liver damage is a key event in the pathogenesis of many chronic human liver diseases, such as liver transplant rejection, primary biliary cirrhosis, and sclerosing cholangitis. We and other groups have previously reported that galectin-9, one of the β-galactoside binding animal lectins, might be potentially useful in the treatment of T cell-mediated diseases. To evaluate the direct effect of galectin-9 on hepatitis induced by concanavalin A (Con A) administration in mice and to clarify the mechanisms involved, we administered galectin-9 into mice, and evaluated its therapeutic effect on Con A-induced hepatitis. Methodology/Principal Findings Galectin-9 was administrated i.v. to Balb/c mice 30 min before Con A injection. Compared with no treatment, galectin-9 pretreatment significantly reduced serum ALT and AST levels and improved liver histopathology, suggesting an ameliorated hepatitis. This therapeutic effect was not only attributable to a blunted Th1 immune response, but also to an increased number in regulatory T cells, as reflected in a significantly increased apoptosis of CD4+CD25low/int effector T cells and in reduced proinflammatory cytokine levels. Conclusion/Significance Our findings constitute the first preclinical data indicating that interfering with TIM-3/galectin-9 signaling in vivo could ameliorate Con A-induced hepatitis. This strategy may represent a new therapeutic approach in treating human diseases involving T cell activation.
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Affiliation(s)
- Kun Lv
- Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, People's Republic of China.
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The stat3/socs3a pathway is a key regulator of hair cell regeneration in zebrafish. [corrected]. J Neurosci 2012; 32:10662-73. [PMID: 22855815 DOI: 10.1523/jneurosci.5785-10.2012] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
All nonmammalian vertebrates studied can regenerate inner ear mechanosensory receptors (i.e., hair cells) (Corwin and Cotanche, 1988; Lombarte et al., 1993; Baird et al., 1996), but mammals possess only a very limited capacity for regeneration after birth (Roberson and Rubel, 1994). As a result, mammals experience permanent deficiencies in hearing and balance once their inner ear hair cells are lost. The mechanisms of hair cell regeneration are poorly understood. Because the inner ear sensory epithelium is highly conserved in all vertebrates (Fritzsch et al., 2007), we chose to study hair cell regeneration mechanism in adult zebrafish, hoping the results would be transferrable to inducing hair cell regeneration in mammals. We defined the comprehensive network of genes involved in hair cell regeneration in the inner ear of adult zebrafish with the powerful transcriptional profiling technique digital gene expression, which leverages the power of next-generation sequencing ('t Hoen et al., 2008). We also identified a key pathway, stat3/socs3, and demonstrated its role in promoting hair cell regeneration through stem cell activation, cell division, and differentiation. In addition, transient pharmacological inhibition of stat3 signaling accelerated hair cell regeneration without overproducing cells. Taking other published datasets into account (Sano et al., 1999; Schebesta et al., 2006; Dierssen et al., 2008; Riehle et al., 2008; Zhu et al., 2008; Qin et al., 2009), we propose that the stat3/socs3 pathway is a key response in all tissue regeneration and thus an important therapeutic target for a broad application in tissue repair and injury healing.
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Laliena A, San Miguel B, Crespo I, Alvarez M, González-Gallego J, Tuñón MJ. Melatonin attenuates inflammation and promotes regeneration in rabbits with fulminant hepatitis of viral origin. J Pineal Res 2012; 53:270-8. [PMID: 22506987 DOI: 10.1111/j.1600-079x.2012.00995.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The objective of the present study was to investigate the effect of melatonin on the liver inflammatory and regenerative response in an animal model of fulminant hepatic failure (FHF) of viral origin. Rabbits were experimentally infected with 2×10(4) hemagglutination units of a rabbit hemorrhagic disease virus (RHDV) isolate and received melatonin at two concentrations of 10 or 20mg/kg at 0, 12 and 24hr postinfection. RHDV infection induced an inflammatory response, with increased expression of toll-like receptor 4, high-mobility group box (HMGB)1, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and C-reactive protein, and decreased expression of decay accelerating factor (DAF/CD55). These effects were significantly reduced by melatonin. Matrix metalloproteinase-9 expression was also lowered in melatonin-treated rabbits. RHDV infection inhibited the hepatic regenerative/proliferative response, with a reduced expression of hepatocyte growth factor (HGF), epidermal growth factor, platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor and their receptors; these responses were prevented by melatonin administration. Melatonin treatment also resulted in reduced expression of phosphorylated Janus kinase and enhanced expression of extracellular mitogen-activated protein kinase (ERK) and signal transducer and activator of transcription (STAT) 3. Our findings show that anti-inflammatory effects and stimulation of regenerative mechanisms contribute to the beneficial effects of melatonin in rabbits with experimental infection by RHDV and support a potential hepatoprotective role of melatonin in FHF.
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Gao B, Wang H, Lafdil F, Feng D. STAT proteins - key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver. J Hepatol 2012; 57:430-41. [PMID: 22504331 PMCID: PMC3399024 DOI: 10.1016/j.jhep.2012.01.029] [Citation(s) in RCA: 146] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Revised: 12/15/2011] [Accepted: 01/02/2012] [Indexed: 12/12/2022]
Abstract
Since its discovery in the early 1990s, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway has been found to play key roles in regulating many key cellular processes such as survival, proliferation, and differentiation. There are seven known mammalian STAT family members: STAT1, 2, 3, 4, 5a, 5b, and 6. In the liver, activation of these STAT proteins is critical for anti-viral defense against hepatitis viral infection and for controlling injury, repair, inflammation, and tumorigenesis. The identification of functions for these STAT proteins has increased our understanding of liver disease pathophysiology and treatments, while also suggesting new therapeutic modalities for managing liver disease.
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Affiliation(s)
- Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Hua Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA, 20892
| | - Fouad Lafdil
- Laboratory of Liver Pathophysiology, INSERM, U955, Créteil, F-94000 France,Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, F-94000 France
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA, 20892
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Feng D, Kong X, Weng H, Park O, Wang H, Dooley S, Gershwin ME, Gao B. Interleukin-22 promotes proliferation of liver stem/progenitor cells in mice and patients with chronic hepatitis B virus infection. Gastroenterology 2012; 143:188-98.e7. [PMID: 22484119 PMCID: PMC3384505 DOI: 10.1053/j.gastro.2012.03.044] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Revised: 03/06/2012] [Accepted: 03/29/2012] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Proliferation of liver stem/progenitor cells (LPCs), which can differentiate into hepatocytes or biliary epithelial cells, is often observed in chronically inflamed regions of liver in patients. We investigated how inflammation might promote proliferation of LPCs. METHODS We examined the role of interleukin (IL)-22, a survival factor for hepatocytes, on proliferation of LPCs in patients with chronic hepatitis B virus (HBV) infection and in mice. Proliferation of LPCs in mice was induced by feeding a diet that contained 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). RESULTS Hepatic expression of IL-22 was increased in patients with HBV and correlated with the grade of inflammation and proliferation of LPCs. Mice on the DDC diet that overexpressed an IL-22 transgene specifically in liver (IL-22TG), or that were infected with an IL-22-expressing adenovirus, had increased proliferation of LPCs. Signal transducer and activator of transcription (STAT) 3, a component of the IL-22 signaling pathway, was activated in LPCs isolated from DDC-fed IL-22TG mice. Deletion of STAT3 from livers of IL-22TG mice reduced proliferation of LPCs. In addition, the receptors IL-22R1 and IL-10R2 were detected on epithelial cell adhesion molecule(+)CD45(-) LPCs isolated from DDC-fed wild-type mice. Culture of these cells with IL-22 activated STAT3 and led to cell proliferation, but IL-22 had no effect on proliferation of STAT3-deficient EpCAM(+)CD45(-) LPCs. IL-22 also activated STAT3 and promoted proliferation of cultured BMOL cells (a mouse LPC line). CONCLUSIONS In livers of mice and patients with chronic HBV infection, inflammatory cells produce IL-22, which promotes proliferation of LPCs via STAT3. These findings link inflammation with proliferation of LPCs in patients with HBV infection.
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Affiliation(s)
- Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Xiaoni Kong
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Honglei Weng
- Molecular Hepatology, II. Medical Clinic, Faculty of Medicine Mannheim at Heidelberg University, Germany
| | - Ogyi Park
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Hua Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Steven Dooley
- Molecular Hepatology, II. Medical Clinic, Faculty of Medicine Mannheim at Heidelberg University, Germany
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
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Sánchez-Sevilla L, Mendieta-Condado E, Hernández-Muñoz R. High dosing of α-tocopherol inhibits rat liver regeneration by modifying signal transducer and activator of transcription protein expression and its correlation with cell redox state and retinoid metabolism. Exp Biol Med (Maywood) 2012; 237:811-21. [DOI: 10.1258/ebm.2012.011405] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Lipid peroxidation (LP) promoted by partial hepatectomy (PH) is qualitatively distinct among subcellular fractions and temporally transient, probably being a necessary physiological event for rat liver regeneration. In fact, α-tocopherol (vitamin E [VE]) exerts adverse effects, partially inhibiting PH-induced rat liver regeneration and inducing decreased cyclin D1 expression. The phosphorylation of signal transducer and activator of transcription (STAT) factors 1 and 3 are involved in DNA synthesis and cyclin D1 expression after PH, which is stimulated by production of retinoic acid (RA). Hence, this study was aimed at addressing these events, and its association with cell redox state and oxidative stress, probably underlying VE effects on rat liver regeneration. PH-enhanced activation of STAT proteins, mainly as activated STAT-3, significantly change the cytoplasmic pool for STATs. The latter was associated to a more reduced cytoplasmic redox state and increased alcohol dehydrogenase (ADH)-mediated retinol oxidation to RA. Whereas α-tocopherol promoted minor changes in the parameters tested when administered to sham (control)-animals, pretreatment with VE blocked the PH-induced increase of reactive oxygen species (ROS), altering the pattern of STAT protein activation, blunting RA formation by decreased ADH activity, inducing higher liver caspase-3 activity and increasing tumor necrosis factor- α concentrations, while levels of interleukin-6 were decreased; altogether coinciding with disturbed PH-promoted changes on the liver redox state. In conclusion, altered activation and translocation of STAT-1 and -3 proteins and inhibited retinoid metabolism seem to be involved in the VE-induced inhibition of rat liver regeneration. Data suggest that a PH-induced increase of ROS could participate in the activation of STAT factors, retinoid metabolism and changes in the cell redox state during proliferation of liver cells.
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Affiliation(s)
- Lourdes Sánchez-Sevilla
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Apdo. Postal 70-243, Ave. Universidad # 3000, Copilco, México 04510, D.F., Mexico
| | - Edgar Mendieta-Condado
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Apdo. Postal 70-243, Ave. Universidad # 3000, Copilco, México 04510, D.F., Mexico
| | - Rolando Hernández-Muñoz
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Apdo. Postal 70-243, Ave. Universidad # 3000, Copilco, México 04510, D.F., Mexico
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27
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Feng D, Park O, Radaeva S, Wang H, Yin S, Kong X, Zheng M, Zakhari S, Kolls JK, Gao B. Interleukin-22 ameliorates cerulein-induced pancreatitis in mice by inhibiting the autophagic pathway. Int J Biol Sci 2012; 8:249-57. [PMID: 22253568 PMCID: PMC3258564 DOI: 10.7150/ijbs.3967] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2011] [Accepted: 01/01/2012] [Indexed: 02/06/2023] Open
Abstract
Pancreatitis occurs when digestive enzymes are activated in the pancreas. Severe pancreatitis has a 10-30% mortality rate. No specific treatments for pancreatitis exist now. Here, we discovered that interleukin-22 (IL-22) may have therapeutic potential in treating acute and chronic pancreatitis. Wild-type and IL-22 knockout mice were equally susceptible to cerulein-induced acute and chronic pancreatitis, whereas liver-specific IL-22 transgenic mice were completely resistant to cerulein-induced elevation of serum digestive enzymes, pancreatic necrosis and apoptosis, and inflammatory cell infiltration. Treatment of wild-type mice with recombinant IL-22 or adenovirus IL-22 markedly attenuated the severity of cerulein-induced acute and chronic pancreatitis. Mechanistically, we show that the protective effect of IL-22 on pancreatitis was mediated via the induction of Bcl-2 and Bcl-X(L), which bind to Beclin-1 and subsequently inhibit autophagosome formation to ameliorate pancreatitis. In conclusion, IL-22 ameliorates cerulein-induced pancreatitis by inhibiting the autophagic pathway. IL-22 could be a promising therapeutic drug to treat pancreatitis.
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Affiliation(s)
- Dechun Feng
- 1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Ogyi Park
- 1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Svetlana Radaeva
- 2. Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Hua Wang
- 1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Shi Yin
- 1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Xiaoni Kong
- 1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Mingquan Zheng
- 3. Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Sam Zakhari
- 2. Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Jay K. Kolls
- 3. Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Bin Gao
- 1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
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Enhanced liver regeneration in IL-10-deficient mice after partial hepatectomy via stimulating inflammatory response and activating hepatocyte STAT3. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:1614-21. [PMID: 21435447 DOI: 10.1016/j.ajpath.2011.01.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2010] [Revised: 12/20/2010] [Accepted: 01/04/2011] [Indexed: 12/14/2022]
Abstract
Emerging evidence suggests that proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), play a critical role in the initiation and progression of liver regeneration; however, relatively little is known about the role of anti-inflammatory cytokine IL-10 in liver regeneration after partial hepatectomy (PHx). Here, we examined the role of IL-10 in liver regeneration using a model of PHx in several strains of genetically modified mice. After PHx, expression of IL-10 mRNA in the liver and spleen was significantly elevated. Such elevation was diminished in TLR4 mutant mice. Compared with wild-type mice, IL-10(-/-) mice had higher levels of expression of proinflammatory cytokines (IL-6, TNF-α, and IFN-γ) and inflammatory markers (CCR2 and F4/80) in the liver, as well as higher serum levels of proinflammatory cytokines after PHx. The number of neutrophils and macrophages was also higher in the livers of IL-10(-/-) mice than in wild-type mice after PHx. Liver regeneration as determined by BrdU incorporation after PHx was higher in IL-10(-/-) mice than in wild-type mice, which was associated with higher levels of activation of IL-6 downstream signal STAT3 in the liver. An additional deletion of STAT3 in hepatocytes significantly reduced liver regeneration in IL-10(-/-) mice after PHx. Collectively, IL-10 plays an important role in negatively regulating liver regeneration via limiting inflammatory response and subsequently tempering hepatic STAT3 activation.
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DeLeve LD, Jaeschke H, Kalra VK, Asahina K, Brenner DA, Tsukamoto H. 15th International Symposium on Cells of the Hepatic Sinusoid, 2010. Liver Int 2011; 31:762-72. [PMID: 21645207 PMCID: PMC4388239 DOI: 10.1111/j.1478-3231.2011.02527.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
This is a meeting report of the presentations given at the 15th International Symposium on Cells of the Hepatic Sinusoid, held in 2010. The areas covered include the contributions of the various liver cell populations to liver disease, molecular and cellular targets involved in steatohepatitis, hepatic fibrosis and cancer and regenerative medicine. In addition to a review of the science presented at the meeting, this report provides references to recent literature on the topics covered at the meeting.
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Affiliation(s)
- Laurie D DeLeve
- Division of Gastrointestinal and Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA 90069, USA.
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Yan S, Wang L, Liu N, Wang Y, Chu Y. Critical role of interleukin-17/interleukin-17 receptor axis in mediating Con A-induced hepatitis. Immunol Cell Biol 2011; 90:421-8. [PMID: 21691280 DOI: 10.1038/icb.2011.59] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Concanavalin A (Con A)-induced hepatitis is thought to be a T-cell-mediated disease with active destruction of liver cells. Interleukin (IL)-17 is a cytokine produced principally by CD4(+) T cells. However, whether IL-17/IL-17 receptor (IL-17/IL-17R)-mediated responses are involved in T-cell-mediated Con A-induced liver injury remains unclear. In this study, we found that IL-17 expression was highly elevated in liver tissues during Con A-induced hepatitis. The increased levels of IL-17 were paralleled with the severity of liver injury reflected by Alanine aminotransaminase and histological assay as well as the secretion of tumor necrosis factor (TNF)-α and IL-6. Blockage of IL-17 significantly ameliorated Con A-induced hepatitis, while overexpression of IL-17 systemically resulted in massive hepatocyte necrosis in mice. Furthermore, overexpression of an IL-17R immunoglobulin G1 fusion protein significantly attenuated liver inflammation after acute Con A treatment. High expression of IL-17R on Kupffer cells was also observed along with the production of cytokines including TNF-α and IL-6. Inhibition of Kupffer cells by gadolinium chloride completely prevented Con A-induced liver injury and cytokine release. Finally, IL-17-expressing CD4(+) T and natural killer T cells were greatly increased in Con A-injected mice compared with that in controls. Overall, our results indicate that IL-17R signaling is critically involved in the pathogenesis in Con A-induced hepatitis, and blockade of IL-17/IL-17R signaling pathway may represent a novel therapeutic intervention in human autoimmune-related hepatitis.
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Affiliation(s)
- Shu Yan
- Department of Immunology, Shanghai Medical College, Key Laboratory of Molecular Medicine of Ministry of Education, Fudan University, Shanghai, PR China
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Wang H, Lafdil F, Wang L, Park O, Yin S, Niu J, Miller AM, Sun Z, Gao B. Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:714-24. [PMID: 21684247 DOI: 10.1016/j.ajpath.2011.05.005] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Revised: 04/25/2011] [Accepted: 05/02/2011] [Indexed: 12/18/2022]
Abstract
Aberrantly hyperactivated STAT3 has been found in human liver cancers as an oncogene; however, STAT3 has also been shown to exert hepatoprotective effects during liver injury. The balancing act that STAT3 plays between hepatoprotection and liver tumorigenesis remains poorly defined. In this study, the diethylnitrosamine (DEN)-induced liver tumor model and the chronic carbon tetrachloride (CCl(4))-induced liver fibrosis model were both used to investigate the role of STAT3 in liver tumorigenesis. Hepatocyte-specific STAT3 knockout mice were resistant to liver tumorigenesis induced by a single DEN injection, whose tumorigenesis was associated with minimal chronic liver inflammation, injury, and fibrosis. In contrast, long-term CCl(4) treatment resulted in severe hepatic oxidative damage, inflammation, and fibrosis but rarely induced liver tumor formation in wild-type mice. Despite the oncogenic function of STAT3 in DEN-induced liver tumor, hepatocyte-specific STAT3 knockout mice were more susceptible to liver tumorigenesis after 16 weeks of CCl(4) injection, which was associated with higher levels of liver injury, inflammation, fibrosis, and oxidative DNA damage compared with wild-type mice. These findings suggest that the hepatoprotective feature of STAT3 prevents hepatic damage and fibrosis under the condition of persistent inflammatory stress, consequently suppressing injury-driven liver tumor initiation. Once liver tumor cells have developed, STAT3 likely acts as an oncogenic factor to promote tumor growth.
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Affiliation(s)
- Hua Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA
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Wang H, Lafdil F, Kong X, Gao B. Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target. Int J Biol Sci 2011; 7:536-50. [PMID: 21552420 PMCID: PMC3088876 DOI: 10.7150/ijbs.7.536] [Citation(s) in RCA: 208] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Accepted: 04/18/2011] [Indexed: 12/12/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated by many cytokines and growth factors and plays a key role in cell survival, proliferation, and differentiation. STAT3 activation is detected virtually in all rodent models of liver injury and in human liver diseases. In this review, we highlight recent advances of STAT3 signaling in liver injury, steatosis, inflammation, regeneration, fibrosis, and hepatocarcinogenesis. The cytokines and small molecules that activate STAT3 in hepatocytes may have therapeutic benefits to treat acute liver injury, fatty liver disease, and alcoholic hepatitis, while blockage of STAT3 may have a therapeutic potential to prevent and treat liver cancer.
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Affiliation(s)
- Hua Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
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Cheng CW, Duwaerts CC, van Rooigen N, Wintermeyer P, Mott S, Gregory SH. NK cells suppress experimental cholestatic liver injury by an interleukin-6-mediated, Kupffer cell-dependent mechanism. J Hepatol 2011; 54:746-52. [PMID: 21129806 PMCID: PMC3060960 DOI: 10.1016/j.jhep.2010.07.018] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Revised: 07/26/2010] [Accepted: 07/29/2010] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIMS Natural killer (NK) cells are innate immune effector cells first characterized by their ability to lyse susceptible tumor cells. Recent studies demonstrated their role in initiating and modulating adaptive immunity. NK cells represent a larger percentage of the lymphoid population in liver than other organs, suggesting that hepatic NK cells express some unique function. Here, we examined the response of NK cells to liver injury that occurs in a mouse model of biliary obstruction. METHODS Bile duct ligations (BDL) were performed in mice previously depleted or not depleted of NK cells. NK cell activation, interleukin (IL)-6 mRNA expression and protein production by Kupffer cells, and the ability of exogenous IL-6 to ameliorate liver injury in NK cell-depleted mice, were determined. RESULTS The number of activated hepatic NK cells increased markedly following BDL. Activation was suppressed in mice rendered Kupffer cell-depleted prior to ligation. Increased liver injury occurred in NK cell-depleted mice correlating with a reduction in IL-6 production. Purified Kupffer cells, obtained from NK cell-depleted or anti-interferon (IFN)-γ monoclonal antibody-pretreated mice following BDL, produced less IL-6 in culture than did Kupffer cells derived from control animals. In culture, hepatic NK cells derived from BDL mice stimulated IFN-γ-dependent IL-6 production by Kupffer cells; splenic NK cells obtained from the same animals had a negligible effect. Treatment with recombinant murine IL-6 reduced liver injury in BDL, NK cell-depleted mice. CONCLUSIONS Hepatic NK cells suppress cholestatic liver injury by stimulating Kupffer cell-dependent IL-6 production.
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Affiliation(s)
- Chao-Wen Cheng
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, 02903
| | - Caroline C. Duwaerts
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, 02903
| | - Nico van Rooigen
- Department of Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands
| | - Philip Wintermeyer
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, 02903
| | - Stephanie Mott
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, 02903
| | - Stephen H. Gregory
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, 02903
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Miller AM, Horiguchi N, Jeong WI, Radaeva S, Gao B. Molecular mechanisms of alcoholic liver disease: innate immunity and cytokines. Alcohol Clin Exp Res 2011; 35:787-93. [PMID: 21284667 DOI: 10.1111/j.1530-0277.2010.01399.x] [Citation(s) in RCA: 136] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases worldwide, causing fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma. In the past few decades, significant progress has been made in our understanding of the molecular mechanisms underlying alcoholic liver injury. Activation of innate immunity components such as Kupffer cells, LPS/TLR4, and complements in response to alcohol exposure plays a key role in the development and progression of alcoholic liver disease (ALD). LPS activation of Kupffer cells also produces IL-6 and IL-10 that may play a protective role in ameliorating ALD. IL-6 activates signal transducer and activator of transcription 3 (STAT3) in hepatocytes and sinusoidal endothelial cells, while IL-10 activates STAT3 in Kupffer cells/macrophages, subsequently protecting against ALD. In addition, alcohol consumption also inhibits some components of innate immunity such as natural killer (NK) cells, a type of cells that play key roles in anti-viral, anti-tumor, and anti-fibrotic defenses in the liver. Ethanol inhibition of NK cells likely contributes significantly to the pathogenesis of ALD. Understanding the roles of innate immunity and cytokines in alcoholic liver injury may provide insight into novel therapeutic targets in the treatment of alcoholic liver disease.
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Affiliation(s)
- Andrew M Miller
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA
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Role of IL-6 trans-signaling in CCl₄induced liver damage. Biochim Biophys Acta Mol Basis Dis 2010; 1802:1054-61. [PMID: 20691261 DOI: 10.1016/j.bbadis.2010.07.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2010] [Revised: 07/20/2010] [Accepted: 07/29/2010] [Indexed: 02/08/2023]
Abstract
Interleukin-6 (IL-6) plays an important role in liver regeneration and protection against liver damage. In addition to IL-6 classic signaling via membrane bound receptor (mIL-6R), IL-6 signaling can also be mediated by soluble IL-6R (sIL-6R) thereby activating cells that do not express membrane bound IL-6R. This process has been named trans-signaling. IL-6 trans-signaling has been demonstrated to operate during liver regeneration. We have developed methods to specifically block or mimic IL-6 trans-signaling. A soluble gp130 protein (sgp130Fc) exclusively inhibits IL-6 trans-signaling whereas an IL-6/sIL-6R fusion protein (Hyper-IL-6) mimics IL-6 trans-signaling. Using these tools we investigate the role of IL-6 trans-signaling in CCl₄ induced liver damage. Blockade of IL-6 trans-signaling during CCl₄ induced liver damage led to higher liver damage, although induction of Cyp4502E1 and thus bioactivation of CCl₄ was unchanged. Depletion of neutrophils resulted in reduced liver transaminase levels irrespective of IL-6 trans-signaling blockade. Furthermore, IL-6 trans-signaling was important for refilling of hepatocyte glycogen stores, which were depleted 24 h after CCl₄ treatment. We conclude that IL-6 trans-signaling via the soluble IL-6R is important for the physiologic response of the liver to CCl₄ induced chemical damage.
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Wei H, Wei H, Wang H, Tian Z, Sun R. Activation of natural killer cells inhibits liver regeneration in toxin-induced liver injury model in mice via a tumor necrosis factor-alpha-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 2010; 299:G275-82. [PMID: 20448144 DOI: 10.1152/ajpgi.00026.2010] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver lymphocytes are enriched in natural killer (NK) cells, and activation of NK cells by injection of polyinosinic-polycytidylic acid (poly I:C) inhibits liver regeneration in the partial hepatectomy model via production of IFN-gamma. However, the role of NK cells in liver regeneration in a model of carbon tetrachloride (CCl(4))-induced liver injury remains unknown. In this study, we investigated the effect of activation of NK cells induced by poly I:C on liver regeneration in the CCl(4) model. Administration of poly I:C suppressed liver regeneration in CCl(4)-treated mice. Depletion of NK cells but not Kupffer cells or T cells restored liver regeneration in poly I:C/CCl(4)-treated mice. Poly I:C and CCl(4) cotreatment synergistically induced accumulation of NK cells in the liver and NK cell production of IFN-gamma and tumor necrosis factor (TNF)-alpha. Serum levels of these two cytokines were also synergistically induced after poly I:C and CCl(4) treatment. Finally, blockage of TNF-alpha but not IFN-gamma restored liver regeneration in poly I:C/CCl(4)-treated mice. Taken together, these findings suggest that poly I:C treatment inhibits liver regeneration in the CCl(4)-induced liver injury model via induction of NK cell production of TNF-alpha.
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Affiliation(s)
- Hairong Wei
- Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, University of Science and Technology of China, 443 Huangshan Rd., Hefei City, Anhui 230027, People's Republic of China
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