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Journal of Hepatology Jul 2021Interleukin (IL)-20 and IL-22 belong to the IL-10 family. IL-10 is a well-documented anti-inflammatory cytokine while IL-22 is well known for epithelial protection and...
BACKGROUND & AIMS
Interleukin (IL)-20 and IL-22 belong to the IL-10 family. IL-10 is a well-documented anti-inflammatory cytokine while IL-22 is well known for epithelial protection and its antibacterial function, showing great therapeutic potential for organ damage; however, the function of IL-20 remains largely unknown.
METHODS
Il20 knockout (Il20) mice and wild-type littermates were generated and injected with Concanavalin A (ConA) and Klebsiella pneumoniae (K.P.) to induce acute hepatitis and bacterial infection, respectively.
RESULTS
Il20 mice were resistant to acute hepatitis and exhibited selectively elevated levels of the hepatoprotective cytokine IL-6. Such selective inhibition of IL-6 by IL-20 was due to IL-20 targeting hepatocytes that produce high levels of IL-6 but a limited number of other cytokines. Mechanistically, IL-20 upregulated NAD(P)H: quinone oxidoreductase 1 (NQO1) expression and subsequently promoted the protein degradation of transcription factor IκBζ, resulting in selective downregulation of the IκBζ-dependent gene Il6 as well several other IκBζ-dependent genes including lipocalin-2 (Lcn2). Given the important role of IL-6 and LCN2 in limiting bacterial infection, we examined the effect of IL-20 on bacterial infection and found Il20 mice were resistant to K.P. infection and exhibited elevated levels of hepatic IκBζ-dependent antibacterial genes. Moreover, IL-20 upregulated hepatic NQO1 by binding to IL-22R1/IL-20R2 and activating ERK/p38MAPK/NRF2 signaling pathways. Finally, the levels of hepatic IL1B, IL20, and IκBζ target genes were elevated, and correlated with each other, in patients with severe alcoholic hepatitis.
CONCLUSIONS
IL-20 selectively inhibits hepatic IL-6 production rather than exerting IL-10-like broad anti-inflammatory properties. Unlike IL-22, IL-20 aggravates acute hepatitis and bacterial infection. Thus, anti-IL-20 therapy could be a promising option to control acute hepatitis and bacterial infection.
LAY SUMMARY
Several interleukin (IL)-20 family cytokines have been shown to play important roles in controllimg inflammatory responses, infection and tissue damage, but the role of IL-20 remains unclear. Herein, we elucidated the role of IL-20 in liver disease and bacterial infection. We show that IL-20 can aggravate hepatitis and bacterial infection; thus, targeting IL-20 holds promise for the treatment of patients with liver disease.
Topics: Adaptor Proteins, Signal Transducing; Animals; Bacterial Infections; Drug Discovery; Gene Expression Regulation; Hepatitis; Hepatitis, Alcoholic; Humans; Interleukin-1beta; Interleukins; Liver; Mice; Mice, Knockout; NAD(P)H Dehydrogenase (Quinone); Proteolysis; Up-Regulation
PubMed: 33610678
DOI: 10.1016/j.jhep.2021.02.004 -
Journal of Hepatology Aug 2018
Topics: Bile Acids and Salts; Cholestasis; Fibroblast Growth Factors; Hepatitis, Alcoholic; Humans; Non-alcoholic Fatty Liver Disease
PubMed: 29792896
DOI: 10.1016/j.jhep.2018.05.012 -
Disease Models & Mechanisms Dec 2020Alcoholic hepatitis (AH) is the dramatic acute presentation of alcoholic liver disease, with a 15% mortality rate within 28 days in severe cases. Research into AH has...
Alcoholic hepatitis (AH) is the dramatic acute presentation of alcoholic liver disease, with a 15% mortality rate within 28 days in severe cases. Research into AH has been hampered by the lack of effective and reproducible murine models that can be operated under different regulatory frameworks internationally. The liquid Lieber-deCarli (LdC) diet has been used as a means of delivery of alcohol but without any additional insult, and is associated with relatively mild liver injury. The transcription factor nuclear factor-erythroid 2-related factor 2 () protects against oxidative stress, and mice deficient in this molecule are suggested to be more sensitive to alcohol-induced injury. We have established a novel model of AH in mice and compared the nature of liver injury in C57/BL6 wild-type (WT) versus mice. Our data showed that both WT and mice demonstrate robust weight loss, and an increase in serum transaminase, steatosis and hepatic inflammation when exposed to diet and ethanol. This is accompanied by an increase in peripheral blood and hepatic myeloid cell populations, fibrogenic response and compensatory hepatocyte regeneration. We also noted characteristic disturbances in hepatic carbohydrate and lipid metabolism. Importantly, use of mice did not increase hepatic injury responses in our hands, and female WT mice exhibited a more-reproducible response. Thus, we have demonstrated that this simple murine model of AH can be used to induce an injury that recreates many of the key human features of AH - without the need for challenging surgical procedures to administer ethanol. This will be valuable for understanding of the pathogenesis of AH, for testing new therapeutic treatments or devising metabolic approaches to manage patients whilst in medical care.This article has an associated First Person interview with the joint first authors of the paper.
Topics: Animals; Disease Models, Animal; Ethanol; Fatty Liver; Female; Hepatitis, Alcoholic; Hepatocytes; Inflammation; Mice, Inbred C57BL; NF-E2-Related Factor 2; Regeneration
PubMed: 33067186
DOI: 10.1242/dmm.046383 -
Hepatology International Jul 2016Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide. ALD encompasses a spectrum of disorders including asymptomatic... (Review)
Review
Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide. ALD encompasses a spectrum of disorders including asymptomatic steatosis, steatohepatitis, fibrosis, cirrhosis and its related complications, and the acute-on-chronic state of alcoholic hepatitis. While multidisciplinary efforts continue to be aimed at curbing progression of this spectrum of disorders, there is an urgent need to focus our efforts on effective therapeutic interventions for alcoholic hepatitis (AH), the most severe form of ALD. AH is characterized by an abrupt development of jaundice and complications related to liver insufficiency and portal hypertension in patients with heavy alcohol intake. The mortality of patients with severe AH is very high (20-50 % at 3 months). The current therapeutic regimens are limited. The development of new therapies requires translational studies in human samples and suitable animal models that reproduce clinical and histological features of human AH. This review article summarizes the clinical syndrome, pre-clinical translational tools, and pathogenesis of AH at a molecular and cellular level, with the aim of identifying new targets of potential therapeutic intervention.
Topics: Animals; Disease Models, Animal; Hepatitis, Alcoholic; Humans; Molecular Targeted Therapy; Translational Research, Biomedical
PubMed: 27072540
DOI: 10.1007/s12072-015-9701-6 -
Liver International : Official Journal... Mar 2020
Topics: Ethanol; Hepatitis, Alcoholic; Humans; Prognosis; Recurrence
PubMed: 32124541
DOI: 10.1111/liv.14343 -
The American Journal of Pathology Apr 2016Alcohol-induced liver damage is a major burden for most societies, and murine studies can provide a means to better understand its pathogenesis and test new therapies.... (Review)
Review
Alcohol-induced liver damage is a major burden for most societies, and murine studies can provide a means to better understand its pathogenesis and test new therapies. However, there are many models reported with widely differing phenotypes, not all of which fully regenerate the spectrum of human disease. Thus, it is important to understand the implications of these variations to efficiently model human disease. This review critically appraises key articles in the field, detailing the spectrum of liver damage seen in different models, and how they relate to the phenotype of disease seen in patients. A range of different methods of alcohol administration have been studied, ranging from ad libitum consumption of alcohol and water to modified diets (eg, Lieber deCarli liquid diet). Other feeding regimens have taken more invasive routes using intragastric feeding tubes to infuse alcohol directly into the stomach. Notably, models using wild-type mice generally produce a milder phenotype of liver damage than those using genetically modified mice, with the exception of the chronic binge-feeding model. We recommend panels of tests for consideration to standardize end points for the evaluation of the severity of liver damage-key for comparison of models of injury, testing of new therapies, and subsequent translation of findings into clinical practice.
Topics: Acute Disease; Animals; Disease Models, Animal; Ethanol; Fatty Liver, Alcoholic; Hepatitis, Alcoholic; Humans; Liver Diseases, Alcoholic
PubMed: 26835538
DOI: 10.1016/j.ajpath.2015.12.003 -
World Journal of Gastroenterology Nov 2015Acute alcoholic hepatitis (AAH) is a serious complication of alcohol misuse and has high short term mortality. It is a clinical syndrome characterised by jaundice and... (Review)
Review
Acute alcoholic hepatitis (AAH) is a serious complication of alcohol misuse and has high short term mortality. It is a clinical syndrome characterised by jaundice and coagulopathy in a patient with a history of recent heavy alcohol use and is associated with profound immune dysfunction with a primed but ineffective immune response against pathogens. Here, we review the current knowledge of the pathogenesis and immune defects of AAH and identify areas requiring further study. Alcohol activates the immune system primarily through the disruption of gut tight junction integrity allowing the escape of pathogen-associated molecular particles (PAMPs) into the portal venous system. PAMPs stimulate cells expressing toll-like receptors (mainly myeloid derived cells) and initiate a network of intercellular signalling by secretion of many soluble mediators including cytokines and chemokines. The latter coordinates the infiltration of neutrophils, monocytes and T cells and results in hepatic stellate cell activation, cellular damage and hepatocyte death by necrosis or apoptosis. On the converse of this immune activation is the growing evidence of impaired microbial defence. Neutrophils have reduced phagocytic capacity and oxidative burst and there is recent evidence that T cell exhaustion plays a role in this.
Topics: Acute Disease; Alcohol Drinking; Animals; Bacterial Translocation; Chemokines; Granulocyte Colony-Stimulating Factor; Hepatitis, Alcoholic; Humans; Immunity, Mucosal; Inflammation Mediators; Intestines; Liver; Prognosis; Risk Factors; Signal Transduction; Th17 Cells; Toll-Like Receptors
PubMed: 26576079
DOI: 10.3748/wjg.v21.i42.11904 -
Annals of Hepatology 2024Alcohol is the leading cause of preventable liver morbidity and mortality worldwide, as it is also the most frequent cause of advanced liver disease. Alcohol-associated... (Review)
Review
Alcohol is the leading cause of preventable liver morbidity and mortality worldwide, as it is also the most frequent cause of advanced liver disease. Alcohol-associated liver disease (ALD) covers different phenotypes ranging from steatosis to the development of inflammation (steatohepatitis), fibrosis and ultimately, in a proportion of patients, the development of liver cirrhosis and its associated complications. ALD has a complex pathogenesis that includes the interplay of both genetic and environmental factors, yet the precise mechanisms are largely unknown. Alcohol-associated hepatitis (AH) is a severe clinical presentation of ALD, which is characterized by abrupt jaundice and clinical decompensations of liver disease. AH occurs in a percentage of patients with underlying ALD and active alcohol consumption. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD and halt the progression of the disease, therefore alcohol abstinence is the most effective measure to improve prognosis in this patient population. In this regard, alcohol cessation remains the first-line treatment in all stages of alcohol disease. In patients with advanced ALD nonresponding to medical therapy, liver transplantation is the only approach that improves prognosis, and it should be considered in patients with decompensated cirrhosis. In the last years, AH has emerged as a new indication of early liver transplantation in non-responders to medical therapy, with promising results in highly selected patients. In this review, we provide an update on the epidemiology, risk factors, natural history, diagnosis, pathogenesis, and current treatments for ALD, taking into account the importance of assessing and managing alcohol consumption as the etiological factor and the main driver of prognosis in patients with ALD.
Topics: Humans; Liver Diseases, Alcoholic; Hepatitis, Alcoholic; Risk Factors; Liver; Alcohol Drinking; Fatty Liver; Ethanol
PubMed: 37832648
DOI: 10.1016/j.aohep.2023.101162 -
Clinical and Molecular Hepatology Oct 2020Alcohol-associated liver disease (ALD), which ranges from mild disease to alcohol-associated hepatitis and cirrhosis, is the most prevalent type of chronic liver disease... (Review)
Review
Alcohol-associated liver disease (ALD), which ranges from mild disease to alcohol-associated hepatitis and cirrhosis, is the most prevalent type of chronic liver disease and a leading cause of morbidity and mortality worldwide. Accumulating evidence reveals that programmed cell death (PCD) plays a crucial role in progression of ALD involving crosstalk between hepatocytes and immune cells. Multiple pathways of PCD, including apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis, are reported in ALD. Interestingly, PCD pathways are intimately linked and interdependent, making it difficult to therapeutically target a single pathway. This review clarifies the multiple types of PCD occurring in liver and focuses on crosstalk between hepatocytes and innate immune cells in ALD.
Topics: Apoptosis; Autophagy; Hepatitis, Alcoholic; Humans; Liver Diseases, Alcoholic; Pyroptosis
PubMed: 32951412
DOI: 10.3350/cmh.2020.0142 -
Journal of the Royal College of... Oct 1977Acute alcoholic hepatitis is an anatomical (fatty liver with sclerosing hyaline necrosis) and a clinical (hepatomegaly with a variety of symptoms of hepatic failure)...
Acute alcoholic hepatitis is an anatomical (fatty liver with sclerosing hyaline necrosis) and a clinical (hepatomegaly with a variety of symptoms of hepatic failure) entity arising out of chronic alcoholism, and of a typically 'pre-cirrhotic' state. Although fatal in 25% of acute cases due to failure of homeostasis, it often leaves a centrilobular scarring necrosis which in more than 60% of cases progresses to nodular cirrhosis. Continued alcoholism worsens the prognosis. Alcoholic hepatitis may be confused with acute abdominal catastrophes or with a hepatoma. The characteristic Mallory bodies found on liver biopsy are found rarely in non-alcoholic hepatitis. There is no effective treatment for this disease except reduction of alcohol intake; indeed, the disease may become self-perpetuating.
Topics: Acute Disease; Adult; Hepatitis, Alcoholic; Humans; Middle Aged
PubMed: 926058
DOI: No ID Found