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Mohi-Ud-Din R, Mir RH, Sawhney G, Dar MA, Bhat ZA. Possible Pathways of Hepatotoxicity Caused by Chemical Agents. Curr Drug Metab 2020; 20:867-879. [PMID: 31702487 DOI: 10.2174/1389200220666191105121653] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/30/2019] [Accepted: 10/16/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Liver injury induced by drugs has become a primary reason for acute liver disease and therefore posed a potential regulatory and clinical challenge over the past few decades and has gained much attention. It also remains the most common cause of failure of drugs during clinical trials. In 50% of all acute liver failure cases, drug-induced hepatoxicity is the primary factor and 5% of all hospital admissions. METHODS The various hepatotoxins used to induce hepatotoxicity in experimental animals include paracetamol, CCl4, isoniazid, thioacetamide, erythromycin, diclofenac, alcohol, etc. Among the various models used to induce hepatotoxicity in rats, every hepatotoxin causes toxicity by different mechanisms. RESULTS The drug-induced hepatotoxicity caused by paracetamol accounts for 39% of the cases and 13% hepatotoxicity is triggered by other hepatotoxic inducing agents. CONCLUSION Research carried out and the published papers revealed that hepatotoxins such as paracetamol and carbon- tetrachloride are widely used for experimental induction of hepatotoxicity in rats.
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Affiliation(s)
- Roohi Mohi-Ud-Din
- Department of Pharmaceutical Sciences, University of Kashmir, Pharmacognosy Division, Hazratbal, Srinagar 190006, Kashmir, India
| | - Reyaz Hassan Mir
- Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Kashmir, India
| | - Gifty Sawhney
- Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu-Tawi, Jammu 180001, India
| | - Mohd Akbar Dar
- Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Kashmir, India
| | - Zulfiqar Ali Bhat
- Department of Pharmaceutical Sciences, University of Kashmir, Pharmacognosy Division, Hazratbal, Srinagar 190006, Kashmir, India
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Akai S, Oda S, Yokoi T. Strain and interindividual differences in lamotrigine-induced liver injury in mice. J Appl Toxicol 2018; 39:451-460. [PMID: 30325050 DOI: 10.1002/jat.3736] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 09/01/2018] [Accepted: 09/01/2018] [Indexed: 12/24/2022]
Abstract
Lamotrigine (LTG) has been widely prescribed as an antipsychotic drug, although it causes idiosyncratic drug-induced liver injury in humans. LTG is mainly metabolized by UDP-glucuronosyltransferase, while LTG undergoes bioactivation by cytochrome P450 to a reactive metabolite; it is subsequently conjugated with glutathione, suggesting that reactive metabolite would be one of the causes for LTG-induced liver injury. However, there is little information regarding the mechanism of LTG-induced liver injury in both humans and rodents. In this study, we established an LTG-induced liver injury mouse model through co-administration with LTG and a glutathione synthesis inhibitor, l-buthionine-(S,R)-sulfoximine. We found an increase in alanine aminotransferase (ALT) levels (>10 000 U/L) in C57BL/6J mice, with apparent interindividual differences. On the other hand, a drastic increase in ALT was not noted in BALB/c mice, suggesting that the initiation mechanism would be different between the two strains. To examine the cause of interindividual differences, C57BL/6J mice that were co-administered LTG and l-buthionine-(S,R)-sulfoximine were categorized into three groups based on ALT values: no-responder (ALT <100 U/L), low-responder (100 U/L < ALT < 1000 U/L) and high-responder (ALT >1000 U/L). In the high-responder group, induction of hepatic oxidative stress, inflammation and damage-associated molecular pattern molecules in mRNA was associated with vacuolation and karyorrhexis in hepatocytes. In conclusion, we demonstrated that LTG showed apparent strain and interindividual differences in liver injuries from the aspects of initiation and exacerbation mechanisms. These results would support interpretation of the mechanism of LTG-induced liver injury observed in humans.
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Affiliation(s)
- Sho Akai
- Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, 466-8550, Japan
| | - Shingo Oda
- Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, 466-8550, Japan
| | - Tsuyoshi Yokoi
- Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, 466-8550, Japan
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Yu J, Liu L, Zhang H, Wu Y, Pei H, Ma L, Xiong A, Xie C. SKLB023 protects mice against acute liver injury by inhibiting proinflammatory cytokine production in both T cells and macrophages. RSC Adv 2018; 8:33338-33346. [PMID: 35548127 PMCID: PMC9086442 DOI: 10.1039/c8ra03720e] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 09/14/2018] [Indexed: 02/05/2023] Open
Abstract
Acute liver failure is a severe clinical syndrome accompanied with excessive inflammatory response. Our previous study demonstrated that SKLB023, a novel thiazolidinedione derivative, showed potent anti-inflammatory activity in rheumatoid arthritis. The purpose of the present study is to evaluate the protective effect of SKLB023 on lipopolysaccharide (LPS)/D-GalN-induced liver failure and to explore the underlying molecular mechanisms. Our results showed that SKLB023 significantly improved mortality and liver injury as indicated by reduced serum levels of aminotransferases and alleviated pathological damage. Additionally, SKLB023 decreased the percentage of activated T cells and macrophages as well as the serum levels of cytokines in vivo. Furthermore, SKLB023 decreased levels of TNF-α and IL-6 secreted from liver macrophages (Kupffer cells) stimulated by LPS in vitro. Our results indicated that the protective effects of SKLB023 were associated with its significant impact on the inflammatory cytokines, which were produced by both T cells and macrophages. A novel thiazolidinedione derivative SKLB023 offers a potent therapeutic strategy for the treatment of acute liver failure.![]()
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Affiliation(s)
- Jia Yu
- Department of Pharmacy, The Third Affiliated Hospital of Nanchang University Nanchang Jiangxi China
| | - Lili Liu
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University Nanchang Jiangxi China
| | - Huiming Zhang
- Department of Pharmacy, The Third Affiliated Hospital of Nanchang University Nanchang Jiangxi China
| | - Yating Wu
- School of Basic Medical Sciences, Nanchang University 999 Xuefu Road, Honggutang New District Nanchang Jiangxi 330031 China +86-791-83827160 +86-791-83827160
| | - Heying Pei
- State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University Chengdu China
| | - Liang Ma
- State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University Chengdu China
| | - Anwen Xiong
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine Shanghai China
| | - Caifeng Xie
- School of Basic Medical Sciences, Nanchang University 999 Xuefu Road, Honggutang New District Nanchang Jiangxi 330031 China +86-791-83827160 +86-791-83827160.,State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University Chengdu China
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4
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Morita H, Hasunuma R, Hoshino M, Fujihara M, Tanaka S, Yamamoto S, Kumazawa Y. Difference in clearance of exogenously administered smooth-form LPS following host responses among normal, sensitized and LPS-tolerant mice. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/096805199700400605] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Clearance of exogenously administered Salmonella abortus equi LPS from the circulation following induction of host responses, e.g. release of soluble CD14 (sCD14) and TNFα production, were investigated. The endotoxin unit of administered LPS in plasma was monitored by a combined method. After 1 h, more than 80% of injected LPS disappeared from the circulation of normal mice at all doses except a 100 μg dose, but sCD14 in plasma could not yet be detected by Western blotting. Release of sCD14 reached a peak 9 h after LPS injection. According to pretreatment with either Propionibacterium acnes or silver nitrate, the clearance rates of exogenously added LPS from the circulation were accelerated in comparison with the rate in normal mice, but plasma TNF levels were the opposite. In LPS-tolerant mice, LPS clearance and production of TNF and sCD14 was reduced. Pretreatment with anti-CD14 mAb reduced LPS-induced TNF production but did not influence the clearance rates. Taken together, in vivo, sCD14 may not play a critical role for early LPS clearance.
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Affiliation(s)
- H. Morita
- Seikagaku Corp., Chuo-ku, Tokyo, Japan
| | - R. Hasunuma
- Department of Biosciences, School of Science, Kitasato University, Sagamihara, Japan
| | - M. Hoshino
- Department of Biosciences, School of Science, Kitasato University, Sagamihara, Japan
| | - M. Fujihara
- Department of Biochemistry, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan
| | - S. Tanaka
- Seikagaku Corp., Chuo-ku, Tokyo, Japan
| | - S. Yamamoto
- Department of Pathology, Ohita Medical College, Ohita-gun,Japan
| | - Y. Kumazawa
- Department of Biosciences, School of Science, Kitasato University, Sagamihara, Japan, -u.ac.jp
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Abstract
Apoptosis is a prominent feature of liver diseases. Causative factors such as alcohol, viruses, toxic bile acids, fatty acids, drugs, and immune response, can induce apoptotic cell death via membrane receptors and intracellular stress. Apoptotic signaling network, including membrane death receptor-mediated cascade, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, lysosomal permeabilization, and mitochondrial dysfunction, is intermixed each other, but one mechanism may dominate at a particular stage. Mechanisms of hepatic apoptosis are complicated by multiple signaling pathways. The progression of liver disease is affected by the balance between apoptotic and antiapoptotic capabilities. Therapeutic options of liver injury are impacted by the clear understanding toward mechanisms of hepatic apoptosis.
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6
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Molecular mechanisms of hepatic apoptosis. Cell Death Dis 2014; 5:e996. [PMID: 24434519 PMCID: PMC4040708 DOI: 10.1038/cddis.2013.499] [Citation(s) in RCA: 244] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 11/07/2013] [Accepted: 11/07/2013] [Indexed: 02/07/2023]
Abstract
Apoptosis is a prominent feature of liver diseases. Causative factors such as alcohol, viruses, toxic bile acids, fatty acids, drugs, and immune response, can induce apoptotic cell death via membrane receptors and intracellular stress. Apoptotic signaling network, including membrane death receptor-mediated cascade, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, lysosomal permeabilization, and mitochondrial dysfunction, is intermixed each other, but one mechanism may dominate at a particular stage. Mechanisms of hepatic apoptosis are complicated by multiple signaling pathways. The progression of liver disease is affected by the balance between apoptotic and antiapoptotic capabilities. Therapeutic options of liver injury are impacted by the clear understanding toward mechanisms of hepatic apoptosis.
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Abstract
Activation of inflammatory signaling pathways is of central importance in the pathogenesis of alcoholic liver disease (ALD) and nonalcoholic steatohepatitis (NASH). Recent studies demonstrated that Toll-like receptors, the sensors of microbial and endogenous danger signals, are expressed and activated in innate immune cells as well as in parenchymal cells in the liver and thereby contribute to ALD and NASH. In this review, we emphasize the importance of gut-derived endotoxin and its recognition by TLR4 in the liver. The significance of TLR-induced intracellular signaling pathways and cytokine production as well as the contribution of individual cell types to the inflammation is evaluated. The contribution of TLR signaling to the induction of liver fibrosis and to the progression of liver pathology mediated by viral pathogens is reviewed in the context of ALD and NASH.
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Affiliation(s)
- Jan Petrasek
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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Tchaptchet S, Gumenscheimer M, Kalis C, Freudenberg N, Hölscher C, Kirschning CJ, Lamers M, Galanos C, Freudenberg MA. TLR9-dependent and independent pathways drive activation of the immune system by Propionibacterium acnes. PLoS One 2012; 7:e39155. [PMID: 22745710 PMCID: PMC3382180 DOI: 10.1371/journal.pone.0039155] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2012] [Accepted: 05/16/2012] [Indexed: 11/19/2022] Open
Abstract
Propionibacterium acnes is usually a relatively harmless commensal. However, under certain, poorly understood conditions it is implicated in the etiology of specific inflammatory diseases. In mice, P. acnes exhibits strong immunomodulatory activity leading to splenomegaly, intrahepatic granuloma formation, hypersensitivity to TLR ligands and endogenous cytokines, and enhanced resistance to infection. All these activities reach a maximum one week after P. acnes priming and require IFN-γ and TLR9. We report here the existence of a markedly delayed (1-2 weeks), but phenotypically similar TLR9-independent immunomodulatory response to P. acnes. This alternative immunomodulation is also IFN-γ dependent and requires functional MyD88. From our experiments, a role for MyD88 in the IFN-γ-mediated P. acnes effects seems unlikely and the participation of the known MyD88-dependent receptors, including TLR5, Unc93B-dependent TLRs, IL-1R and IL-18R in the development of the alternative response has been excluded. However, the crucial role of MyD88 can partly be attributed to TLR2 and TLR4 involvement. Either of these two TLRs, activated by bacteria and/or endogenously generated ligands, can fulfill the required function. Our findings hint at an innate immune sensitizing mechanism, which is potentially operative in both infectious and sterile inflammatory disorders.
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Affiliation(s)
- Sandrine Tchaptchet
- Department of Developmental Immunology, Max Planck Institute of Immunbiology und Epigenetics, Freiburg, Germany
| | - Marina Gumenscheimer
- Department of Developmental Immunology, Max Planck Institute of Immunbiology und Epigenetics, Freiburg, Germany
| | - Christoph Kalis
- Department of Developmental Immunology, Max Planck Institute of Immunbiology und Epigenetics, Freiburg, Germany
| | | | - Christoph Hölscher
- Division of Infection Immunology, Research Center Borstel, Borstel, Germany
| | | | - Marinus Lamers
- Department of Developmental Immunology, Max Planck Institute of Immunbiology und Epigenetics, Freiburg, Germany
| | - Chris Galanos
- Department of Developmental Immunology, Max Planck Institute of Immunbiology und Epigenetics, Freiburg, Germany
| | - Marina A. Freudenberg
- Department of Developmental Immunology, Max Planck Institute of Immunbiology und Epigenetics, Freiburg, Germany
- * E-mail:
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Fan XP, Zou ZQ, Long B, Guo YM, Wang SK, Jia DX, Xu AL, Li FC, Fan YC, Wang K. Enhanced demethylation of interferon-γ gene promoter in peripheral blood mononuclear cells is associated with acute-on-chronic hepatitis B liver failure. TOHOKU J EXP MED 2011; 224:13-9. [PMID: 21505270 DOI: 10.1620/tjem.224.13] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Acute-on-chronic hepatitis B liver failure (ACHBLF) refers to liver failure occurring in patients with chronic hepatitis B (CHB) related liver diseases. Interferon-γ (IFN-γ) plays an important role in the exacerbation of liver function. However, the exact mechanism, by which IFN-γ mediates ACHBLF, is not fully understood. Forty patients with ACHBLF, fifteen patients with CHB and ten healthy controls were included in this present study. ELISA was performed to measure the level of serum IFN-γ. The methylation status of IFN-γ promoter in peripheral blood mononuclear cells (PBMCs) was determined using methylation-specific PCR. Model for End-stage Liver Disease (MELD) scoring was performed for evaluating the severity of liver failure. The serum level of IFN-γ in patients with ACHBLF or CHB was significantly lower than that in healthy controls, while the serum IFN-γ level in ACHBLF patients was significantly higher than that in CHB patients. In ACHBLF patients, the level of IFN-γ was positively correlated with total bilirubin and MELD score, but negatively correlated with prothrombin time activity. These results suggest the involvement of IFN-γ in the pathogenesis of ACHBLF. Importantly, the degree of methylation of the IFN-γ gene promoter in ACHBLF patients (60%, 24/40) was significantly lower than that in CHB patients (93%, 14/15), but was higher than that in the control group (20%, 2/10). Furthermore, in ACHBLF patients, the serum IFN-γ level was significantly higher in unmethylation group than that in methylation group. In conclusion, enhanced demethylation of IFN-γ gene promoter in PBMCs may be associated with the onset of ACHBLF.
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Affiliation(s)
- Xiao-Peng Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, PR China
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10
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Tchaptchet S, Kirberg J, Freudenberg N, Schamel WWA, Galanos C, Freudenberg MA. Innate, antigen-independent role for T cells in the activation of the immune system by Propionibacterium acnes. Eur J Immunol 2010; 40:2506-16. [PMID: 20690177 DOI: 10.1002/eji.200939860] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Propionibacterium acnes is a human commensal but also an opportunistic pathogen. In mice, P. acnes exerts strong immunomodulatory activities, including formation of intrahepatic granulomas and induction of LPS hypersensitivity. These activities are dependent on P. acnes recognition via TLR9 and subsequent IL-12-mediated IFN-gamma production. We show that P. acnes elicits IL-12p40 and p35 mRNA expression in macrophages, and IFN-gamma mRNA in liver CD4(+) T cells and NK cells. After priming with P. acnes, CD4(+) T cells serve as the major IFN-gamma mRNA source. In the absence of CD4(+) T cells, CD8(+) T cells (regardless of antigenic specificity) or NK cells can produce sufficient IFN-gamma to induce the P. acnes-driven immune effects. Moreover, in the absence of alpha beta T cells, gamma delta T cells also enable the development of strongly enhanced TNF-alpha and IFN-gamma responses to LPS and intrahepatic granuloma formation. Thus, under microbial pressure, different T-cell types, independent of their antigen specificity, exert NK-cell-like functions, which contribute decisively to the activation of the innate immune system.
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11
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Toll-like receptors in the pathogenesis of alcoholic liver disease. Gastroenterol Res Pract 2010; 2010. [PMID: 20827314 PMCID: PMC2933900 DOI: 10.1155/2010/710381] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2010] [Accepted: 07/20/2010] [Indexed: 12/15/2022] Open
Abstract
In the multifactorial pathophysiology of alcoholic liver disease (ALD), inflammatory cascade activation plays a central role. Recent studies demonstrated that Toll-like Receptors, the sensors of microbial and endogenous danger signals, are expressed and activated in innate immune cells as well as in parenchymal cells in the liver and thereby contribute to ALD. In this paper, we discuss the importance of gut-derived endotoxin and its recognition by TLR4. The significance of TLR-induced intracellular signaling pathways and cytokine production as well as the contribution of reactive oxygen radicals is evaluated. The contribution of TLR signaling to induction of liver fibrosis and hepatocellular cancer is reviewed in the context of alcohol-induced liver disease.
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12
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Tasaka S, Kamata H, Miyamoto K, Nakano Y, Shinoda H, Kimizuka Y, Fujiwara H, Hasegawa N, Fujishima S, Miyasho T, Ishizaka A. Intratracheal synthetic CpG oligodeoxynucleotide causes acute lung injury with systemic inflammatory response. Respir Res 2009; 10:84. [PMID: 19772669 PMCID: PMC2761862 DOI: 10.1186/1465-9921-10-84] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2009] [Accepted: 09/23/2009] [Indexed: 12/23/2022] Open
Abstract
Bacterial genome is characterized by frequent unmethylated cytosine-phosphate-guanine (CpG) motifs. Deleterious effects can occur when synthetic oligodeoxynucleotides (ODN) with unmethylated CpG dinucleotides (CpG-ODN) are administered in a systemic fashion. We aimed to evaluate the effect of intratracheal CpG-ODN on lung inflammation and systemic inflammatory response. C57BL/6J mice received intratracheal administration of CpG-ODN (0.01, 0.1, 1.0, 10, or 100 μM) or control ODN without CpG motif. Bronchoalveolar lavage (BAL) fluid was obtained 3 or 6 h or 1, 2, 7, or 14 days after the instillation and subjected to a differential cell count and cytokine measurement. Lung permeability was evaluated as the BAL fluid-to-plasma ratio of the concentration of human serum albumin that was injected 1 h before euthanasia. Nuclear factor (NF)-κB DNA binding activity was also evaluated in lung homogenates. Intratracheal administration of 10 μM or higher concentration of CpG-ODN induced significant inflammatory cell accumulation into the airspace. The peak accumulation of neutrophils and lymphocytes occurred 1 and 2 days after the CpG-ODN administration, respectively. Lung permeability was increased 1 day after the 10 μM CpG-ODN challenge. CpG-ODN also induced nuclear translocation of NF-κB and upregulation of various inflammatory cytokines in BAL fluid and plasma. Histopathology of the lungs and liver revealed acute lung injury and liver damage with necrosis, respectively. Control ODN without CpG motif did not induce any inflammatory change. Since intratracheal CpG-ODN induced acute lung injury as well as systemic inflammatory response, therapeutic strategies to neutralize bacterial DNA that is released after administration of bactericidal agents should be considered.
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Affiliation(s)
- Sadatomo Tasaka
- Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan.
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Kobayashi E, Kobayashi M, Tsuneyama K, Fukami T, Nakajima M, Yokoi T. Halothane-induced liver injury is mediated by interleukin-17 in mice. Toxicol Sci 2009; 111:302-10. [PMID: 19633216 DOI: 10.1093/toxsci/kfp165] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Drug-induced liver injury is a major problem in drug development and clinical drug therapy. In most cases the mechanisms are still unknown, thus, it is difficult to predict or prevent these reactions. It has been known that halothane, an inhaled anesthetic, induces liver injury. To investigate the mechanisms of halothane-induced liver injury, we used a recently established mouse model of liver injury. The expression of transcription factors and cytokines specific for Th1 and Th2 (helper T cells), respectively, were compared between BALB/c and C57BL/6 mice. The mRNA expression ratios of mouse T-bet(a Th1-specific transcription factor)/GATA-binding protein (GATA-3, a Th2-specific transcription factor) and interferon gamma/interleukin (IL)-10 were lower in BALB/c mice compared with C57BL/6 mice, suggesting that a typical Th1 or Th2-dominant response could not be distinguished in halothane-induced liver injury. We observed increases of the plasma IL-17 level and hepatic macrophage inflammatory protein 2 expression in halothane-administrated BALB/c mice, as well as neutrophil infiltration. Neutralization of IL-17 suppressed the hepatotoxic effect of halothane. Administration of recombinant IL-17 (1 microg per mouse, single ip) to the halothane-treated mice resulted in a remarkable increase of alanine and aspartate aminotransferases. In conclusion, we demonstrated that IL-17 is involved in the halothane-induced liver injury.
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Affiliation(s)
- Eisuke Kobayashi
- Drug Metabolism and Toxicology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
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Imbalanced intrahepatic cytokine expression of interferon-gamma, tumor necrosis factor-alpha, and interleukin-10 in patients with acute-on-chronic liver failure associated with hepatitis B virus infection. J Clin Gastroenterol 2009; 43:182-90. [PMID: 18633332 DOI: 10.1097/mcg.0b013e3181624464] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
GOALS This study attempts to determine expressions of intrahepatic proinflammatory and anti-inflammatory cytokines and their secreting immunocytes to evaluate their roles in the pathogenesis of acute-on-chronic liver failure (ACLF) in chronically hepatitis B virus (HBV)-infected patients. BACKGROUND ACLF generally affects patients with established, compensated chronic liver diseases who develop an acute deterioration in liver function. In China, HBV-associated ACLF patients account for more than 80% of ACLF patients owing to a high prevalence of chronic HBV infection. Clinical observation showed that the deterioration of this disease may correlate with host immune responses, but related underlying mechanism remains largely unknown. STUDY In situ expressions of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), and their secreting CD4, CD8 T cells, and Kupffer cells (KCs) were analyzed in the livers of patients with ACLF, chronic hepatitis B (CHB), and normal controls (NC) using immunohistochemistry. RESULTS Intrahepatic proinflammatory IFN-gamma and TNF-alpha expressions were markedly up-regulated in ACLF compared with CHB and NC. However, similar anti-inflammatory IL-10 expressions were observed in ACLF and CHB. IFN-gamma overexpression correlated significantly with increased CD4 and CD8 T-cell accumulation. TNF-alpha up-regulation also correlated significantly with increased KCs. CONCLUSIONS The imbalanced expression of proinflammatory and anti-inflammatory cytokines and increased accumulation of CD4, CD8 T cells, and KCs may contribute to immunopathogenesis in HBV-infected ACLF.
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15
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Masubuchi Y, Sugiyama S, Horie T. Th1/Th2 cytokine balance as a determinant of acetaminophen-induced liver injury. Chem Biol Interact 2008; 179:273-9. [PMID: 19014921 DOI: 10.1016/j.cbi.2008.10.028] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2008] [Revised: 10/16/2008] [Accepted: 10/17/2008] [Indexed: 12/11/2022]
Abstract
Inflammation is an important pathophysiological event in drug-induced liver injury, which is subsequent to metabolic activation and covalent binding of the reactive metabolites to target proteins. Cytokines are recognized as pro- and anti-inflammatory mediators involved in the progression and regression of the toxicity. We thus hypothesized that disturbed balance of Th1/Th2 cytokines exacerbated the drug-induced hepatotoxicity. Acetaminophen-induced liver injury was investigated in two mouse strains, C57BL/6 and BALB/c, which develop predominantly Th1 and Th2 responses, respectively. More severe liver injury after intraperitoneal administration of acetaminophen was observed in C57BL/6 mice than in BALB/c mice. There was no strain difference in metabolism of acetaminophen into its reactive metabolite, N-acetyl-p-benzoquinone imine, which was assessed by early glutathione consumption. Liver mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and IL-6 were measured as pro- and anti-inflammatory cytokines, respectively. TNF-alpha was highly induced 24 h after administration of acetaminophen in C57BL/6 mice, whereas no change in BALB/c mice. On the other hand, liver IL-6 mRNA expression in BALB/c mice was higher than C57BL/6 mice 24 h after the administration. In addition, treatment of CD-1 mice, another susceptible strain, with an anti-inflammatory polyphenol, resveratrol, protected mice against the acetaminophen-induced liver injury, and the mice with attenuated toxicity revealed lower expression of TNF-alpha and higher expression of IL-6. It is therefore suggested that acetaminophen-induced liver injury is associated with Th1-dominant response in Th1/Th2 cytokine balance, and TNF-alpha may play a pathological role in the toxicity.
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Affiliation(s)
- Yasuhiro Masubuchi
- Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Shiomi-cho, Choshi, Chiba, 288-0025, Japan
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16
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Song YH, Liu Q, Lv ZP, Chen YY, Zhou YC, Sun XG. Protection of a polysaccharide from Salvia miltiorrhiza, a Chinese medicinal herb, against immunological liver injury in mice. Int J Biol Macromol 2008; 43:170-5. [DOI: 10.1016/j.ijbiomac.2008.04.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2008] [Revised: 04/23/2008] [Accepted: 04/25/2008] [Indexed: 12/19/2022]
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Invernizzi P, Bianchi I, Locati M, Bonecchi R, Selmi C. Cytokines in Liver Health and Disease. LIVER IMMUNOLOGY 2008:83-93. [DOI: 10.1007/978-1-59745-518-3_8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Margenthaler JA, Ku G, Flye MW. Interleukin-12 regulates natural killer cell-dependent Propionibacterium acnes-primed, lipopolysaccharide-induced liver injury. Hepatol Res 2008; 38:183-93. [PMID: 18197879 DOI: 10.1111/j.1872-034x.2007.00214.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Interleukin (IL)-12, produced primarily by macrophage/monocytes, modulates mature T and natural killer (NK) cell functions, including cytotoxicity and cytokine production. METHODS To determine the role of IL-12 in Propionibacterium acnes (P. acnes)-primed, lipopolysaccharide (LPS)-induced liver injury, mice were injected with an anti-IL-12 monoclonal antibody (mAb) 1 and 2 days before P. acnes injection (day 0) or 5 and 6 days before LPS challenge (day 7). The survival rates, plasma cytokine levels, and liver mononuclear cell phenotypes were evaluated for the mice treated with and without anti-IL-12 mAb. RESULTS The observed mortality with P. acnes-primed, LPS-induced liver injury in C57BL/6 (B6) mice was 100%, but was reduced to 0% in interferon (IFN)-gamma receptor-deficient mice and B6 mice treated with anti-IL-12 mAb on 1 and 2 days before P. acnes exposure (day 0). The plasma IFN-gamma levels weresignificantly lower (P < 0.05), and significantly less ( approximately 90% reduction) hepatic infiltrating mononuclear and NK1.1 cells were also found in the IL-12 mAb-treated, P. acnes-primed mice. The plasma cytokine levels after LPS challenge and in vitro cytokine release by liver mononuclear cells were significantly lower (P < 0.05) in the mice treated with anti-IL-12 mAb prior to P. acnes exposure. The in vivo administration of anti-NK1.1 mAb also improved survival in this liver injury model. CONCLUSION IL-12-regulated IFN-gamma production is crucial during the priming phase by P. acnes, but not at the time of the subsequent LPS challenge. NK1.1(+)CD3(-)CD4(-) NK or NK1.1(+)CD3(+)CD4(-) NKT cells are important in this model of liver injury.
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Affiliation(s)
- Julie A Margenthaler
- Department of Surgery, Washington University School of Medicine, St Louis, Missouri, USA
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Kuroda E, Noguchi J, Doi T, Uematsu S, Akira S, Yamashita U. IL-3 is an important differentiation factor for the development of prostaglandin E2-producing macrophages between C57BL/6 and BALB/c mice. Eur J Immunol 2007; 37:2185-95. [PMID: 17628861 DOI: 10.1002/eji.200737041] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
We have previously reported that peritoneal and splenic macrophages from Th2-dominant BALB/c mice produced higher amounts of prostaglandin (PG) E2 than cells from C57BL/6 mice. In this study, we investigated how macrophages from BALB/c mice acquire the ability of enhanced PGE2 production, using bone marrow-derived macrophages differentiated by M-CSF, GM-CSF or IL-3. There is no strain difference in PGE2 production by GM-CSF- and M-CSF-differentiated macrophages; however, IL-3-differentiated macrophages from BALB/c mice produced higher amounts of PGE2 and lower amounts of type I cytokines than cells from C57BL/6 mice. IL-3-differentiated macrophages from BALB/c mice expressed larger amounts of mRNA of membrane-bound (microsomal) PGE synthase-1 (mPGES-1). The amounts of PGE2 produced by macrophages were significantly reduced in mPGES-1-deficient mice, and these mice displayed enhanced Th1 responses after Propionibacterium acnes treatment compared with wild-type mice. Microarray analysis revealed 63 genes that are differentially expressed more than fivefold in macrophages between C57BL/6 and BALB/c mice. These results indicate that mPGES-1-mediated PGE2 produced by macrophages regulates immune responses, and IL-3 is an important factor for the differentiation of macrophages that produce higher amounts of PGE2 through mPGES-1 activity in BALB/c mice.
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Affiliation(s)
- Etsushi Kuroda
- Department of Immunology and Parasitology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
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Velayudham A, Hritz I, Dolganiuc A, Mandrekar P, Kurt-Jones E, Szabo G. Critical role of toll-like receptors and the common TLR adaptor, MyD88, in induction of granulomas and liver injury. J Hepatol 2006; 45:813-24. [PMID: 16935388 DOI: 10.1016/j.jhep.2006.06.017] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2006] [Revised: 05/24/2006] [Accepted: 06/15/2006] [Indexed: 12/20/2022]
Abstract
BACKGROUND/AIMS Toll-like receptors (TLR) recognize pathogens and regulate innate immune activation. Here, we investigated the roles of TLR9 and the common TLR adaptor, MyD88, in liver injury. METHODS C57BL6, TLR9(-/-), IFNgamma(-/-) or MyD88(-/-) mice were primed with Propionibacterium acnes, TLR9 (CpG) or TLR2 (lipoteichoic acid) ligands followed by LPS challenge. ALT, cytokines and liver histology were assessed. RESULTS Selective priming through TLR9 but not TLR2 induced granulomas, elevated serum ALT, and sensitized C57BL6 mice to increased LPS-induced serum IL-6, IL-12 and IFNgamma levels. Further, TLR2 and TLR9 ligands synergized in induction of granulomas and sensitization to LPS-induced inflammation. IFNgamma induction by P. acnes, TLR2 and TLR9 ligands required MyD88. In MyD88(-/-) mice P. acnes failed to induce granulomas and both MyD88 and TLR9 deficiency prevented P. acnes-induced sensitization to LPS. Increased mRNA expression of genes of the TLR4 signaling complex (TLR4, CD14, MD-2, and MyD88) and the NADPH complexes (p47phox, p67phox, gp91phox, and p22phox) was induced by priming with P. acnes or TLR9 plus TLR2 suggesting mechanisms for LPS sensitization and liver injury. CONCLUSIONS TLR9+/-TLR2 activation via MyD88-dependent pathways plays a pivotal role in liver sensitization and granuloma formation.
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Affiliation(s)
- Arumugam Velayudham
- Liver Center, Department of Medicine, University of Massachusetts Medical School, Plantation Street, Worcester, MA 01605, USA
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Zou Y, Yang Y, Li J, Li W, Wu Q. Prevention of hepatic injury by a traditional Chinese formulation, BJ-JN, in mice treated with Bacille-Calmette-Guérin and lipopolysaccharide. JOURNAL OF ETHNOPHARMACOLOGY 2006; 107:442-8. [PMID: 16697540 DOI: 10.1016/j.jep.2006.04.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2005] [Revised: 03/17/2006] [Accepted: 04/03/2006] [Indexed: 05/09/2023]
Abstract
The hepatoprotective effects of BJ-JN (a traditional Chinese formulation) were evaluated in Bacille-Calmette-Guérin and lipopolysaccharide (BCG/LPS)-induced immunological liver injury (ILI) in mice. BJ-JN (0.75, 1.5, 3 g/kg) was administered via gavage daily for 10 days. Liver index (liver weight/body weight), serum levels of alanine aminotransferase (ALT), hepatic nitric oxide (NO), malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, splenocyte proliferation, production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) by peritoneal macrophages, and histopathologic changes of the liver were evaluated following the 10 days treatment. BJ-JN (0.75, 1.5, 3 g/kg) effectively reduced the BCG/LPS-induced elevated liver index, serum ALT levels, hepatic NO and MDA content, and restored hepatic SOD activity in ILI mice. BJ-JN treatment also alleviated diminished splenocyte proliferation induced by concanavalin A (ConA) and repressed abnormally high levels of TNF-alpha and IL-1 from peritoneal macrophages. The histopathological analysis suggested that BJ-JN reduced the degree of liver injury of ILI mice. These results suggest that BJ-JN has a protective and therapeutic effect on ILI mice, which might be associated with its antioxidant properties, ability to reduce NO production and immunoregulatory function.
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Affiliation(s)
- Yuhong Zou
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
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22
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Sharma RP, He Q, Johnson VJ, Suzuki H. Mice lacking both TNFα receptors show increased constitutive expression of IFNγ: A possible reason for lack of protection from fumonisin B1 hepatotoxicity☆. Cytokine 2006; 34:260-70. [PMID: 16884913 DOI: 10.1016/j.cyto.2006.06.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2006] [Revised: 06/01/2006] [Accepted: 06/02/2006] [Indexed: 10/24/2022]
Abstract
Fumonisin B1 is a mycotoxin prevalent in corn that produces species-, gender-, and organ-specific diseases. Mice lacking TNFalpha receptor (TNFR) 1 or 2 exhibited a diminished hepatotoxic response to fumonisin B1; however, the protection was lost when both TNFRs were deleted. We therefore investigated the constitutive expression of selected apoptotic factors and their response to fumonisin B1 in the liver from mice lacking both TNFRs (DRKO). Compared to their wild-type (WT) counterparts the DRKO strain had a higher constitutive mRNA expression of interferon (IFN)gamma, Fas, and interleukin (IL)-18. The mRNA expression of Bcl-2 was also higher in DRKO than in WT mice. The mRNA expression of IL-1 receptor antagonist (IL-1Ra) was decreased; that of TNF-related apoptosis-inducing ligand (TRAIL) was dramatically reduced. Induction of most apoptotic genes in response to fumonisin B1 was similar in both WT and DRKO strains; except in DRKO mice it was greater for Max and lesser for IL-1Ra than that in WT strain. Fumonisin B1 hepatotoxicity in DRKO mice was reduced by pretreatment with anti-IFNgamma antibody. It appears that in the absence of TNFalpha signaling other apoptotic pathways become operative; particularly the increase of IFNgamma, Fas and IL-18 may compensate for the loss of TNFalpha effects. Fumonisin B1 toxicity therefore appears to be a complex phenomenon that may utilize more than one cytotoxic pathway consequent to sphingoid deregulation; a higher expression of IFNgamma and other apoptotic factors in DRKO may be responsible for the observed fumonisin hepatotoxicity.
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MESH Headings
- Alanine Transaminase/metabolism
- Animals
- Antibodies/immunology
- Apoptosis/drug effects
- Apoptosis/genetics
- Aspartate Aminotransferases/metabolism
- Fumonisins/toxicity
- Gene Expression/genetics
- Interferon-gamma/genetics
- Interferon-gamma/immunology
- Interferon-gamma/metabolism
- Liver/cytology
- Liver/drug effects
- Liver/metabolism
- Mice
- Mice, Knockout
- Receptors, Tumor Necrosis Factor/deficiency
- Receptors, Tumor Necrosis Factor/genetics
- Receptors, Tumor Necrosis Factor/metabolism
- Receptors, Tumor Necrosis Factor, Type I
- Receptors, Tumor Necrosis Factor, Type II/deficiency
- Receptors, Tumor Necrosis Factor, Type II/genetics
- Receptors, Tumor Necrosis Factor, Type II/metabolism
- Sphingosine/analogs & derivatives
- Sphingosine/metabolism
- Tumor Necrosis Factor Decoy Receptors
- Tumor Necrosis Factor-alpha/genetics
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Affiliation(s)
- Raghubir P Sharma
- Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
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Noguchi J, Kuroda E, Yamashita U. Strain difference of murine bone marrow-derived mast cell functions. J Leukoc Biol 2006; 78:605-11. [PMID: 16126842 DOI: 10.1189/jlb.1104676] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Mast cells play an important role for the induction and the expression of allergic responses. In this report, we studied the strain difference of bone marrow-derived murine mast cell (BMMC) functions in vitro. BMMC were induced by in vitro culture of bone marrow cells from BALB/c and C57BL/6 mice with interleukin (IL)-3 for 4 weeks, stimulated with immunoglobulin E antibody and antigen, and mediators and cytokines released in the culture supernatant were assayed. BMMC from C57BL/6 mice released a higher amount of granule-associated mediators, beta-hexosaminidase, and histamine than that from BALB/c mice. The expression of mRNA of histidine decarboxylase was higher in C57BL/6 mice. Conversely, the productions of newly synthesized mediators, prostaglandin D2 (PGD2), IL-6, and monocyte chemoattractant protein-1, and the mRNA expression of IL-5 were higher in BALB/c BMMC than C57BL/6 BMMC. Although mRNA and protein expression levels of cyclooxygenase-2 were equal in two strains, both expression levels of hematopoietic PGD synthase (hPGDS) were higher in BALB/c BMMC. Mast cells, freshly obtained from mice, also showed the same strain difference concerning the mediator release. These results indicate that the strain difference exists in mast cell functions in mice, and this difference can be considered to induce the susceptibility difference to allergic reactions in mouse strains.
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Affiliation(s)
- Junko Noguchi
- School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu 807-8555, Japan
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Chen ZX, Zhang SJ, Lao SX, Hu HT, Zhang CY, Guan SH, Gu YL. He Jie Tang in the treatment of chronic hepatitis B patients. World J Gastroenterol 2005; 11:6638-43. [PMID: 16425357 PMCID: PMC4355757 DOI: 10.3748/wjg.v11.i42.6638] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effect of He Jie Tang (decoction for medication) on serum levels of T lymphocyte subsets, NK cell activity and cytokines in chronic hepatitis B patients.
METHODS: Eighty-five patients with chronic hepatitis B were divided randomly into two groups. Fifty patients in group I were treated with He Jie Tang (HJT) and 35 patients in group II were treated with combined medication. The levels of T-lymphocyte subsets (CD3+, CD4+, CD8+), NK cell activity, cytokines (TNF-α, IL-8, sIL-2R) were observed before and after the treatment. Another 20 normal persons served as group 3.
RESULTS: The level of CD4+ cells and NK cell activity were lower, whereas the level of CD8+ cells in patients was higher than that in normal persons (t = 2.685, 3.172, and 2.754 respectively; P<0.01). The levels of TNF-α, IL-8, and sIL-2R in chronic hepatitis B patients were higher than those in normal persons (t = 3.526, 3.170, and 2.876 respectively; P<0.01). After 6 months of treatment, ALT, AST, and TB levels in the two groups were obviously decreased (t = 3.421, 3.106, and 2.857 respectively; P<0.01). The level of CD4+ cells and NK cell activity were increased whereas the level of CD8+ cells decreased (t = 2.179, 2.423, and 2.677 respectively; P<0.05) in group I. The levels of TNF-α, IL-8, and sIL-2R in group I were decreased significantly after the treatment (t = 2.611, 2.275, and 2.480 respectively; P<0.05) but had no significant difference in group II after the treatment (t = 1.906, 1.833, and 2.029 respectively; P>0.05). The total effective rate had no significant difference between the two groups (X2 = 2.882, P>0.05) but the markedly effective rate was significantly different between the two groups (X2 = 5.340, P<0.05).
CONCLUSION: HJT is effective in treating chronic hepatitis B. HJT seems to exert its effect by improving the cellular immune function and decreasing inflammatory cytokines in chronic hepatitis B patients. The function of HJT in protecting liver function in the process of eliminating virus needs to be further studied.
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Affiliation(s)
- Ze-Xiong Chen
- Department of Traditional Chinese Medicine, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China
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Bobrowski WF, McDuffie JE, Sobocinski G, Chupka J, Olle E, Bowman A, Albassam M. Comparative methods for multiplex analysis of cytokine protein expression in plasma of lipopolysaccharide-treated mice. Cytokine 2005; 32:194-8. [PMID: 16257531 DOI: 10.1016/j.cyto.2005.09.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2005] [Revised: 06/29/2005] [Accepted: 09/14/2005] [Indexed: 10/25/2022]
Abstract
Changes in circulating cytokines might serve as predictors of compound-evoked inflammatory responses. CD-1 mice were treated with lipopolysaccharide (LPS; 0.2 ml of 0.25 mg/ml, intraperitoneal) for subsequent expression measurement of plasma cytokine protein expression at 24-h post-treatment using multiple antibody Western blot, and at both 2-h and 24-h post-treatment using antibody array and suspension bead array. Antibody array provided a semi-qualitative assessment and suggested significantly increased expression of GCSF at 2-h post-treatment and GCSF, IL-6, IL-12, MCP-1, MCP-5, RANTES and sTNFR1 at 24-h post-treatment. Densitometric analysis of multiple antibody Western blots provided a semi-quantitative assessment and indicated significantly increased expression of IL-6, IL-12, IL-17, GCSF, eotaxin, and MCP-2 at 24-h post-treatment. The suspension bead array yielded statistically significant cytokine protein expression increases for IL-6, IL-10, IFNgamma and TNFalpha at both 2-h and 24-h post-treatments, while significant expression at 24-h post-treatment only was noted for IL-1beta, IL-5, IL-12 and GM-CSF. Suspension bead array provided the greatest range of detection, revealing subtle increased expression of GM-CSF, IL-1beta, IL-5, IL-10, TNFalpha and IFNgamma at 24-h post-treatment, not detected by antibody array or multiple antibody Western blot. Suspension bead array proved to be the best method for detection of LPS-evoked changes in plasma cytokine levels.
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Affiliation(s)
- Walter F Bobrowski
- Pfizer Global Research and Development, 2800 Plymouth Road, 35/183, Ann Arbor, MI 48105, USA.
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Xu HB, Gong YP, Cheng J, Chu YW, Xiong SD. CXCL16 participates in pathogenesis of immunological liver injury by regulating T lymphocyte infiltration in liver tissue. World J Gastroenterol 2005; 11:4979-85. [PMID: 16124049 PMCID: PMC4321913 DOI: 10.3748/wjg.v11.i32.4979] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of CXCL16 in the pathogenesis of immunological liver injury and to explore the possible mechanism of T lymphocyte infiltration regulated by CXCL16.
METHODS: Immunological liver injury in murine model was induced by Bacille Calmette-Guerin and lipopolysaccharide. Expression pattern and distribution of CXCL16 were examined by real-time quantitative RT-PCR and immunohistochemical analysis. Anti-CXCL16 antibody was administrated in vivo to investigate its effect on T-cell recruitment and acute hepatic necrosis. The survival of murine model was also evaluated.
RESULTS: The murine immunological liver injury model was successfully established. CXCL16 expression increased and predominantly distributed in periportal areas and vascular endothelia in injured liver tissues. Administration of anti-CXCL16 Ab protected the mice from death and acute liver damage. Approximately 70% of the mice survived for 72 h in the anti-CXCL16 Ab treatment group, whereas 80% died within 72 h in control Ab group. The number of liver-infiltrating T lymphocytes was significantly reduced from 1.01×107 to 3.52×106/liver, compared with control Ab treatment.
CONCLUSION: CXCL16 is involved in immunological liver injury by regulating T lymphocyte infiltration in liver tissue.
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Affiliation(s)
- Huan-Bin Xu
- Department of Immunology, Shanghai Medical College of Fudan University, Shanghai 200032, China
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Xu H, Xu W, Chu Y, Gong Y, Jiang Z, Xiong S. Involvement of up-regulated CXC chemokine ligand 16/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein in endotoxin-induced lethal liver injury via regulation of T-cell recruitment and adhesion. Infect Immun 2005; 73:4007-16. [PMID: 15972488 PMCID: PMC1168580 DOI: 10.1128/iai.73.7.4007-4016.2005] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
A murine model of endotoxin-induced lethal liver injury induced by Mycobacterium bovis BCG plus lipopolysaccharide (LPS) has been widely accepted and used. It has been reported that T cells play an important role in the pathogenesis of liver damage in this model. However, the precise mechanisms involved in regulation of the trafficking of effector T cells need to be elucidated. In the present study, we first reported that CXCL16/SR-PSOX (CXC chemokine ligand 16/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein), a chemokine containing both membrane-anchored and soluble forms, was strongly up-regulated and predominantly distributed in the vascular endothelium in the injured liver tissue in the model. The secretory and membrane-anchored CXCL16/SR-PSOX functioned as a chemokine and an adhesive molecule, respectively, to attract T cells to a tumor necrosis factor alpha-activated endothelial cell line (SVEC) in vitro. To further identify the pathophysiological roles of CXCL16/SR-PSOX in the liver injury, the anti-CXCL16 antibody was administered to the BCG-primed mice before LPS challenge in vivo. Significant protection effects were observed with 70% of mice regarding lethality, the massive necrosis in the liver was reduced, and the intrahepatic infiltrating T cells were significantly inhibited. Taken together, these findings strongly suggest that functional CXCL16/SR-PSOX, as both a chemokine and an adhesion molecule, may be involved in the pathogenesis of the endotoxin-induced lethal liver injury via recruitment and adhesion of activated T cells to the vascular endothelium.
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Affiliation(s)
- Huanbin Xu
- Department of Immunology and Key Laboratory of Molecular Medicine of Ministry of Education, Shanghai Medical College of Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, People's Republic of China
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Yamaguchi A, Togashi Y, Koda T, Nishimura T. [Development of DNA array filter useful for the analysis of Th1/Th2 balance]. NIHON RINSHO MEN'EKI GAKKAI KAISHI = JAPANESE JOURNAL OF CLINICAL IMMUNOLOGY 2005; 28:86-91. [PMID: 15863967 DOI: 10.2177/jsci.28.86] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
DNA arrays are useful for determining the expression levels of a number of genes at once. We utilized this technique to evaluate the Th1/Th2 balance in vivo. Immune responses are controlled by two types of helper T cells, Th1 and Th2. Once the balance of Th1/Th2 immunity is disrupted, various immune diseases can develop. Thus, it is important to evaluate the Th1/Th2 balance in each patient for diagnosis, treatment and/or prophylaxis of immune diseases. We have identified a number of genes specifically expressed in Th1 or Th2 cells, and developed a DNA array filter spotted with these genes. We confirmed that this filter is useful for the evaluation of changes in the immune balance in vivo. Clinical application of this technology may lead to the tailor-made therapy of immune diseases through the evaluation of the immune balance in each patient.
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Affiliation(s)
- Aki Yamaguchi
- Division of immunoregulation, Institute for Genetic Medicine, Hokkaido University
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Nuntaprasert A, Mori Y, Fujita K, Yoneda M, Miura R, Tsukiyama-Kohara K, Kai C. Characterization of specific antibodies and the establishment of sandwich ELISA and ELISPOT systems for swine IL-4. Comp Immunol Microbiol Infect Dis 2004; 27:457-70. [PMID: 15325518 DOI: 10.1016/j.cimid.2004.03.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
We produced four monoclonal antibodies (mAb) and two polyclonal antibodies using the purified cytokine expressed in bacteria and characterized them. Specific binding of each of the mAb and polyclonal antibodies to recombinant swine IL-4 (rSwIL-4) purified from Escherichia coli and baculovirus was demonstrated in an indirect ELISA and/or in western blotting. We established a sandwich enzyme-linked immunosorbent assay (ELISA) for measuring concentration of SwIL-4 in biological samples and established an enzyme-linked immunospot (ELISPOT) assay for detecting IL-4-secreting cells using a mAb and a polyclonal IgG from goat. The detection limit of the sandwich ELISA for SwIL-4 was 78 pg/ml. Using sandwich ELISA, SwIL-4 was detected in the bronchoalveolar lavage fluid (BALF) of pigs experimentally infected with Mycoplasma hyopneumoniae and could quantitate in supernatants of mitogen-stimulated PBMC culture. The ELISPOT system is useful for the detection of IL-4 producing cells in swine PBMC culture.
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Affiliation(s)
- A Nuntaprasert
- Laboratory of Animal Research Center, Institution of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai Minato-ku, Tokyo 108-8639, Japan
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30
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Fukuda K, Takao Y, Miyazaki Y, Itoh K, Yamada A. New type of natural antibodies reactive to cytotoxic T lymphocyte-directed cancer vaccine peptides. Immunobiology 2004; 209:245-53. [PMID: 15518336 DOI: 10.1016/j.imbio.2004.03.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
We recently reported the existence of antibodies (Abs) reactive to cytotoxic T lymphocyte-directed cancer vaccine peptides derived from non-mutated and proliferation-related self-proteins in the sera of healthy donors. The IgG class of these Abs was either lacking or unbalanced in atopic dermatitis patients, although the induction of a specific IgG by peptide vaccination was correlated with long survival in cancer patients, suggesting its positive role in the host defense. To understand the biological features of these Abs, we employed murine models due to the sequence homology of these peptides in human and mouse. Both IgM and IgG classes of these peptide-specific Abs were detected in all of the euthymic mice tested; however, only IgM was found in athymic nu/nu mice, and not in SCID mice. Maintenance of euthymic mice under germ-free conditions resulted in a lack of the IgG class of the Abs in these mice. Ab levels were found to increase with age-maturation, but they decreased under tumor bearing conditions or in cases of graft-versus-host disease. The Abs showed catalytic activity upon hydrogen peroxide (H2O2) production. These results suggest the existence of a novel type of natural Ab that is reactive to cancer vaccine peptides.
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Affiliation(s)
- Kunie Fukuda
- Cancer Vaccine Development Division, Kurume University Research Center for Innovative Cancer Therapy, Japan
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Stadecker MJ, Asahi H, Finger E, Hernandez HJ, Rutitzky LI, Sun J. The immunobiology of Th1 polarization in high-pathology schistosomiasis. Immunol Rev 2004; 201:168-79. [PMID: 15361240 DOI: 10.1111/j.0105-2896.2004.00197.x] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Schistosomiasis is a serious global helminthic disease, in which the main immunopathology consists of a granulomatous and fibrosing reaction against tissue-trapped parasite eggs. The severity of this inflammatory process, the product of a CD4(+) T-cell-mediated immune response against parasite egg antigens, is, however, markedly uneven, both in human patients and among mouse strains in an experimental model. Severe schistosomiasis is associated with persistently elevated pro-inflammatory T-helper-1 (Th1)-type cytokines, whereas milder pathology is present when Th2 cytokines dominate. This scenario is supported by the pronounced pathology resulting from the obliteration of pathways that facilitate Th2 differentiation and by the development of more intense lesions in mouse strains that fail to downregulate the Th1 response. Genetically prone high-pathology mice have a higher proportion of CD4(+) T cells in lymph nodes and granulomas, in which the Th1 phenotype is driven by interleukin-12; they also develop a dominant repertoire against peptide 234-246 of the major Sm-p40 egg antigen, utilizing a strikingly restricted T-cell receptor structure that involves Valpha11.3beta8. In turn, low-pathology mice exhibit enhanced CD4(+) T-cell apoptosis, which contributes to limit pathology. The definition of distinctive immune profiles associated with polar forms of schistosomiasis opens opportunities for targeted immuno-intervention in individuals suffering from or at risk of severe disease.
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Affiliation(s)
- Miguel J Stadecker
- Department of Pathology, Tufts University School of Medicine, Boston, MA, USA.
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Yokoyama M, Yokoyama A, Mori S, Takahashi HK, Yoshino T, Watanabe T, Watanabe T, Ohtsu H, Nishibori M. Inducible histamine protects mice from P. acnes-primed and LPS-induced hepatitis through H2-receptor stimulation. Gastroenterology 2004; 127:892-902. [PMID: 15362044 DOI: 10.1053/j.gastro.2004.06.020] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Inducible histamine and histamine H2-receptors have been suggested to be involved in innate immune response. METHODS We examined a functional role of inducible histamine in the protection against hepatic injury and lethality in Propionibacterium acnes -primed and lipopolysaccharide-induced hepatitis, using histidine decarboxylase knockout and H2-receptor knockout mice. RESULTS Lipopolysaccharide challenge after Propionibacterium acnes priming increased histidine decarboxylase activity in the liver of wild-type mice, associated with a marked elevation of histamine turnover. Histidine decarboxylase-like immunoreactivity was observed in CD68-positive Kupffer cells/macrophages. Treatment of wild-type mice with famotidine or ranitidine but not d -chlorpheniramine augmented hepatic injury and inhibited the survival rate significantly. The same dose of Propionibacterium acnes and lipopolysaccharide induced severe hepatitis and high lethality in histidine decarboxylase knockout and H2-receptor knockout mice; the former were rescued by the subcutaneous injection of histamine. Immunohistochemical study supported the protective role of histamine against the apoptosis of hepatocytes. Histamine suppressed the expression of IL-18 and tumor necrosis factor alpha in the liver, leading to the reduced plasma levels of cytokines including IL-18, TNF-alpha, IL-12, IFN-gamma, and IL-6. CONCLUSIONS These findings as a whole indicated that endogenously produced histamine in Kupffer cells/macrophages plays a very important role in preventing excessive innate immune response in endotoxin-induced fulminant hepatitis through the stimulation of H2-receptors.
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Affiliation(s)
- Minori Yokoyama
- Department of Pharmacology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
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Yajima T, Nishimura H, Saito K, Kuwano H, Yoshikai Y. Overexpression of Interleukin-15 increases susceptibility to lipopolysaccharide-induced liver injury in mice primed with Mycobacterium bovis bacillus Calmette-Guerin. Infect Immun 2004; 72:3855-62. [PMID: 15213127 PMCID: PMC427448 DOI: 10.1128/iai.72.7.3855-3862.2004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Mice primed with Mycobacterium bovis bacillus Calmette-Guérin (BCG) are highly sensitive to lipopolysaccharide (LPS)-induced liver injury and lethality. We found that interleukin-15 (IL-15) transgenic (Tg) mice primed with BCG were more susceptible to LPS-induced liver injury than non-Tg mice. The numbers of CD44+ CD8+ T cells expressing intracellular gamma interferon (IFN-gamma) significantly increased in the livers of BCG-primed IL-15 Tg mice after LPS injection, and the depletion of CD8+ T cells from BCG-primed IL-15 Tg mice completely abolished the susceptibility to LPS-induced lethality. Liver T cells from BCG-primed IL-15 Tg mice produced IFN-gamma in vitro in response to LPS, which was inhibited by the addition of anti-IL-12 monoclonal antibody (MAb). In vivo treatment with anti-IL-12 MAb inhibited the appearance of CD44+ CD8+ T cells expressing intracellular IFN-gamma after LPS injection. These results suggest that the overexpression of IL-15 increases susceptibility to LPS-induced liver injury in BCG-primed mice via bystander activation of CD8+ T cells.
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Affiliation(s)
- Toshiki Yajima
- Division of Host Defense, Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
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Li Z, Oben JA, Yang S, Lin H, Stafford EA, Soloski MJ, Thomas SA, Diehl AM. Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis. Hepatology 2004; 40:434-41. [PMID: 15368448 DOI: 10.1002/hep.20320] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
It is not known why natural killer T (NKT) cells, which modulate liver injury by regulating local cytokine production, are reduced in leptin-deficient ob/ob mice. NKT cells express adrenoceptors. Thus, we hypothesize that the low norepinephrine (NE) activity of ob/ob mice promotes depletion of liver NKT cells, thereby sensitizing ob/ob livers to lipopolysaccharide (LPS) toxicity. To evaluate this hypothesis, hepatic NKT cells were quantified in wild-type mice before and after treatment with NE inhibitors, and in dopamine beta-hydroxylase knockout mice (which cannot synthesize NE) and ob/ob mice before and after 4 weeks of NE supplementation. Decreasing NE activity consistently reduces liver NKT cells, while increasing NE has the opposite effect. Analysis of hepatic and thymic NKT cells in mice of different ages demonstrate an age-related accumulation of hepatic NKT cells in normal mice, while liver NKT cells become depleted after birth in ob/ob mice, which have increased apoptosis of hepatic NKT cells. NE treatment inhibits apoptosis and restores hepatic NKT cells. In ob/ob mice with reduced hepatic NKT cells, hepatic T and NKT cells produce excessive T helper (Th)-1 proinflammatory cytokines and the liver is sensitized to LPS toxicity. NE treatment decreases Th-1 cytokines, increases production of Th-2 cytokines, and reduces hepatotoxicity. Studies of CD1d-deficient mice, which lack the receptor required for NKT cell development, demonstrate that they are also unusually sensitive to LPS hepatotoxicity. In conclusion, low NE activity increases hepatic NKT cell apoptosis and depletes liver NKT cells, promoting proinflammatory polarization of hepatic cytokine production that sensitizes the liver to LPS toxicity.
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Affiliation(s)
- Zhiping Li
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
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Cherñavsky AC, Paladino N, Rubio AE, De Biasio MB, Periolo N, Cuarterolo M, Goñi J, Galoppo C, Cañero-Velasco MC, Muñoz AE, Fainboim H, Fainboim L. Simultaneous expression of th1 cytokines and IL-4 confers severe characteristics to type I autoimmune hepatitis in children. Hum Immunol 2004; 65:683-91. [PMID: 15301856 DOI: 10.1016/j.humimm.2004.03.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2003] [Revised: 03/25/2004] [Accepted: 03/25/2004] [Indexed: 01/30/2023]
Abstract
To investigate the immunopathogenic mechanisms of type I autoimmune hepatitis in children, we analyzed by quantitative or semiquantitative reverse transcription-polymerase chain reaction the expression of cytokines interferon (IFN)-gamma, interleukin (IL)-12p40, IL-18, IL-4, IL-10, and IL-12R beta 2. In addition, liver and peripheral blood was collected to investigate the expression of the natural killer T (NKT) cell marker V alpha 24. The presence of NKT cells in hepatic lesions were also identified by immunohistochemistry. The analysis was performed on liver biopsies from 25 children with type I autoimmune hepatitis. As disease controls, we included six children with hepatitis C virus-related chronic hepatitis and nine control livers. The expression of IFN-gamma and IL-12p40 was not detected in controls but was clearly upregulated in pathologic biopsies. In addition, these samples showed an increased expression of IL-18 (p = 0.0003), IL-4 (p = 0.0055), and IL-12R beta 2 (p = 0.007). Western blot analysis confirmed the expression of IL-12p40 and IL-18. However, for IL-18, we detected only the immature biologically inactive polypeptide. The V alpha 24 transcripts were found increased in the liver (p = 0.0007) where V alpha 24(+) cells were also localized, but decreased in peripheral blood mononuclear cells (p = 0.041). In addition to a type I immune response, NKT cells might play a substantial role in the pathogenesis of type I autoimmune hepatitis in children.
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MESH Headings
- Adolescent
- Autoantibodies/blood
- Biopsy, Needle
- Blood Chemical Analysis
- Blotting, Western
- Child
- Cytokines/genetics
- Cytokines/immunology
- Cytokines/metabolism
- Female
- Gene Expression
- Hepatitis, Autoimmune/genetics
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/pathology
- Humans
- Immunohistochemistry
- Interferon-gamma/genetics
- Interleukin-10/genetics
- Interleukin-10/metabolism
- Interleukin-12/genetics
- Interleukin-12/metabolism
- Interleukin-12 Subunit p40
- Interleukin-18/genetics
- Interleukin-18/metabolism
- Interleukin-4/genetics
- Interleukin-4/immunology
- Interleukin-4/metabolism
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Killer Cells, Natural/pathology
- Leukocytes, Mononuclear/chemistry
- Liver/immunology
- Liver/metabolism
- Liver/pathology
- Male
- Protein Subunits/genetics
- Protein Subunits/metabolism
- Receptors, Antigen, T-Cell, alpha-beta/analysis
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Receptors, Interleukin/genetics
- Receptors, Interleukin/metabolism
- Receptors, Interleukin-12
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/metabolism
- Th1 Cells/immunology
- Th1 Cells/metabolism
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Affiliation(s)
- Alejandra Claudia Cherñavsky
- División Inmunogenética, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Av. Córdoba 2351 (1120) Buenos Aires, Argentina
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Sharma RP, He Q, Johnson VJ, Voss KA. Increased expression of CD95-ligand and other apoptotic signaling factors by fumonisin B1, a hepatotoxic mycotoxin, in livers of mice lacking tumor necrosis factor α. Cytokine 2003; 24:226-36. [PMID: 14596819 DOI: 10.1016/j.cyto.2003.08.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Fumonisin B1 (FB1), a mycotoxin, is a potent inhibitor of ceramide synthase, and produces organ-, species-, and even gender-specific toxic responses in animals. The hepatotoxic response of FB1 in mice involves accumulation of free sphingoid bases and induction of inflammatory cytokines including tumor necrosis factor alpha (TNFalpha). The FB1-induced hepatotoxic responses were reduced in mice lacking TNFalpha receptor (TNFR) 1 or TNFR2. However, the hepatotoxicity was exacerbated in mice lacking TNFalpha. We therefore investigated the modulation of various other apoptotic signaling factors in TNFalpha-knockout (TKO) mice compared to wild-type (WT) strain after repeated daily subcutaneous injections of 2.25 mg/kg FB1 treatment for 5 days. Expression of various signaling genes in liver was evaluated by ribonuclease protection assay. Expression of CD95-ligand (FasL) was more than doubled in TKO animals after FB1 whereas it was unaltered in the WT group. FB1 did not alter CD95 expression in either strain; however, expressions of TRAIL, and downstream signaling factors FADD, TRADD, and caspase 8 were higher in FB1-treated TKO mice than in the corresponding WT animals. The TKO strain had a higher constitutive expression of apoptotic factors except CD95L. In addition to the CD95 and TNFalpha systems, the expression of apoptotic molecules bcl-2, b-myc, c-myc, bax, max, mad and IL1alpha was induced by FB1 in TKO mice to a greater extent than in WT animals; many of these factors also had a higher constitutive expression in TKO animals than WT mice. Results indicated that FB1 can induce CD95 modulated signaling when TNFalpha is absent. Differential constitutive expression of apoptotic genes in TKO mice may explain their increased sensitivity to FB1. These results are important in characterizing the modulating effect of TNFalpha on apoptotic signaling and in explaining the unexpected sensitivity of mice lacking this cytokine in response to hepatotoxic xenobiotics.
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Affiliation(s)
- Raghubir P Sharma
- Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
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Abstract
AIM: To evaluate the abnormal immunity and gene mutation at precore 1896 site in patients with severe hepatitis-B.
METHODS: This study included 23 patients with severe hepatitis-B, 22 patients with acute hepatitis-B and 20 controls. Mutation at precore 1896 site of HBV gene was confirmed with restriction fragment length polymorphism (RFLP) analysis. Cytokines including TNF-α, IFN-γ, IL-6, and IL-8 were measured with ELISA, and T subgroups were detected with alkaline phosphatase anti alkaline phosphatase (APAAP) technique.
RESULTS: In patients with severe hepatitis-B, the infective rate of HBV mutant strain was 52.5% (12/23), and only one patient with acute hepatitis-B was infected with the mutant strain. The percentage of CD8+ T lymphocyte was obviously lower (0.16 ± 0.02%) and the ratio of CD4+/CD8+ was obviously higher (2.35 ± 0.89) in mutant group than in wild-type group (0.28 ± 0.05% and 1.31 ± 0.18%, respectively, P < 0.01 or P < 0.05). The levels of cytokines in patients with severe hepatitis-B were higher (TNF-α 359.0 ± 17.2 ng/L, IFN-γ 234.7 ± 16.5 ng/L, IL-6347.5 ± 31.3 ng/L, IL-8181.1 ± 19.6 ng/L) than those in acute hepatitis-B (TNF-α 220.6 ± 8.9 ng/L, IFN-γ 174.9 ± 12.0 ng/L, IL-6285.8 ± 16.5 ng/L, IL-8118.4 ± 5.1 ng/L, P < 0.01 or 0.05). In patients with severe hepatitis-B, the levels of IFN-γ and IL-6 were higher in mutant group (273.4 ± 26.6 ng/L, 387.7 ± 32.5 ng/L) than in wild-type group (207.8 ± 12.8 ng/L, 300.9 ± 16.3 ng/L). The mortality of patients infected with HBV mutant strain was higher (100%) than that with wild-type (0.9%).
CONCLUSION: In severe hepatitis-B, the infective rate of HBV mutant strain was high. The mutant strain induces more severe immune disorders in host, resulting in the activation of lymphocyte and release of cytokines. HBV DNA mutates easily in response to the altered immunity. Ultimately liver damage is more prominent.
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Affiliation(s)
- Jing-Yan Wang
- Department of Infectious Diseases, the Second Hospital, China Medical University, Shenyang 110004, Liaoning Province, China
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Margenthaler JA, Landeros K, Kataoka M, Eilers M, Ku G, Flye MW. Effects of endotoxin tolerance on Propionibacterium acnes-primed lipopolysaccharide hepatic injury. J Surg Res 2003; 112:102-10. [PMID: 12873441 DOI: 10.1016/s0022-4804(03)00133-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Prior administration of the Gram-positive bacteria Propionibacterium acnes (PA) results in hypersensitivity and hepatocyte necrosis to a subsequent low dose of lipopolysaccharide (LPS). Endotoxin tolerance has been shown to prevent lethality after ischemia/reperfusion injuries, sepsis, and endotoxic shock. We investigated whether prior induction of LPS tolerance could prevent subsequent PA-priming and LPS-induced death. The levels of known effector cytokines possibly responsible for these changes were measured. METHODS C57BL/6 (B6) mice were given heat-killed PA (0.5 mg/mouse) followed 7 days later by LPS (20 microg/mouse). In parallel experiments, B6 mice were pretreated with a single 20 microg/mouse dose of LPS (lethal dose = 800 microg/mouse) 7 days prior to PA priming. Animal survival, liver and spleen weights, and histology were examined. Cytokine levels of the inflammatory cytokines interferon-alpha, tumor necrosis factor-gamma, interleukin (IL)-6, and IL-12 and the anti-inflammatory cytokines IL-4 and IL-10 were measured by enzyme-linked immunosorbent assay and by reverse-transcription polymerase chain reaction. RESULTS Hepatomegaly, splenomegaly, and hepatocyte necrosis with death developed in all PA-primed B6 mice challenged with LPS. However, 83% of B6 mice given a tolerizing dose of LPS prior to PA survived (P < 0.01) without any increase in liver or spleen weights and without histological evidence of necrosis. Markedly decreased in vivo and in vitro inflammatory (interferon-alpha, tumor necrosis factor-gamma, IL-6, and IL-12) cytokine levels corresponded with survival in the LPS-tolerant mice. Endotoxin tolerance and subsequent survival were also associated with an increase in anti-inflammatory (IL-4 and IL-10) mRNA expression. CONCLUSIONS Lethal PA-primed LPS-induced hepatic injury can be prevented by administering a tolerizing dose of LPS prior to PA-priming. LPS protects the liver by preventing hepatic mononuclear cellular infiltration, reducing the production of the toxic proinflammatory cytokines, and inducing the production of endogenous anti-inflammatory cytokines.
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Affiliation(s)
- Julie A Margenthaler
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
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Ludwiczek O, Kaser A, Novick D, Dinarello CA, Rubinstein M, Vogel W, Tilg H. Plasma levels of interleukin-18 and interleukin-18 binding protein are elevated in patients with chronic liver disease. J Clin Immunol 2003. [PMID: 12462332 DOI: 10.1023/a: 1020600230977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Interleukin 18 (IL-18) is a recently described proinflammatory cytokine. In mouse models it has been shown to play a key role in the development of liver injury. IL-18 binding protein (IL-18BP) is a naturally occurring antagonist of IL-18. In this study we investigated whether IL-18/IL-18BP levels are altered in patients with chronic liver disease (CLD). We measured IL-18 and IL-18BP plasma levels in 153 patients with CLD and 41 healthy controls by a specific ELISA. Plasma levels of IL-18 were significantly higher in CLD patients than in healthy controls. Cirrhotics had higher levels than noncirrhotics. IL-18 levels increased with disease progression. IL-18BP plasma levels paralled the increase of IL-18 with disease progression, except in stage Child C cirrhosis. IL-18 and IL-18BP levels were elevated independent of the etiology of CLD. IL-18 and IL-18BP correlated with laboratory parameters of inflammation and liver injury. Plasma levels of IL-18 and its antagonist, IL-18BP, are elevated in CLD and correlate with severity of disease. IL-18BP may not be sufficient to counteract the overwhelming proinflammatory response in end stage liver disease.
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Affiliation(s)
- Othmar Ludwiczek
- University Hospital Innsbruck, Department of Medicine, Division of Gastroenterology and Hepatology, Innsbruck, Austria
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Nakada T, Watanabe K, Jin GB, Triizuk K, Hanawa T. Effect of ninjin-youei-to on Th1/Th2 type cytokine production in different mouse strains. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2003; 30:215-23. [PMID: 12230010 DOI: 10.1142/s0192415x0200034x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Ninjin-youei-to (NYT; ren-shen-yang-rong-tang in Chinese) is a traditional herbal formula, which is widely used in Japan, Korea and China to modulate physiological immunity. The effects of oral administration of NYT on cytokine production from splenocytes were investigated in both C57BL/6 and BALB/c mice in which Th1 and Th2 were dominant, respectively. Splenocytes from C57BL/6 and BALB/c mice, which took NYT orally forfour weeks, were cultured with anti-mouse CD3 mAb, and the supernatant was examined for cytokine production using enzyme-linked immunosorbent assay (ELISA). Administration of NYT to C57BL/6 mice, increased the production of interleukin-4 (IL-4) significantly, and slightly decreased interferon-y (IFN-gamma) production from splenocytes. In contrast, the same treatment significantly increased IFN-gamma secretion from splenocytes of BALB/c mice. No remarkable changes of IL-12 production from splenocytes were observed in either strain of mice. These results suggest that oral administration of NYT ameliorates the excessive inclination of Th1 and Th2 type cytokine production, and NYT may provide a beneficial effects for the treatment of diseases caused by a skewed Th1-Th2 balance in the immune system.
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Affiliation(s)
- Tsutomu Nakada
- Oriental Medicine Research Center of the Kitasato Institute, Japan
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Iwaki T, Sugimura M, Nishihira J, Matsuura T, Kobayashi T, Kanayama N. Recombinant adenovirus vector bearing antisense macrophage migration inhibitory factor cDNA prevents acute lipopolysaccharide-induced liver failure in mice. J Transl Med 2003; 83:561-70. [PMID: 12695559 DOI: 10.1097/01.lab.0000062857.26210.ef] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine involved in delayed hypersensitivity and cellular immunity. MIF also acts as a proinflammatory cytokine and counterregulates the anti-inflammatory effects of glucocorticoids. Exogenous gene transfer mediated by adenovirus is useful to study a particular molecular function as well as to develop gene therapy strategies. A recombinant adenovirus containing sense and antisense murine MIF (mMIF) cDNA inserts was constructed using a cosmid-terminal protein complex method. The sense mMIF adenovirus (AxCA-mMIFS) efficiently induced mMIF in COS-7 cells that endogenously lack mMIF in a dose-dependent manner. In contrast, the antisense mMIF adenovirus (AxCA-mMIFAS) inhibited the expression of mMIF in NIH3T3 cells in a dose-dependent manner. To assess the pathophysiologic role of MIF in acute liver failure, we induced acute onset of liver damage in mice (male Jcl:ICR) by a combined treatment of Bacille Calmette-Guerin (BCG) and lipopolysaccharide (LPS). mMIF level in the liver of mice infected with AxCA-mMIFAS showed a significant reduction in MIF production in response to BCG-LPS compared with mice treated without viral infection and with AxCA-mMIFS. In addition, the immunohistochemical staining demonstrated that F4/80 antigen on macrophage was enhanced in liver infected with AxCA-mMIFS but reduced in liver infected with AxCA-mMIFAS. The staining intensity is correlated with the mMIF antigen level in liver tissue. The survival rate of mice infected with AxCA-mMIFAS was significantly higher than that of mice treated with PBS and infected with AxCA-LacZ in BCG-LPS. These results suggest that inhibition of MIF production, using recombinant adenovirus bearing the antisense MIF gene, reduced the mortality rate in BCG-LPS-induced liver failure in mice. This finding might aid in the further development of gene therapy targeting MIF.
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Affiliation(s)
- Takayuki Iwaki
- Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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Sharma RP, He Q, Meredith FI, Riley RT, Voss KA. Paradoxical role of tumor necrosis factor alpha in fumonisin-induced hepatotoxicity in mice. Toxicology 2002; 180:221-32. [PMID: 12393292 DOI: 10.1016/s0300-483x(02)00376-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Tumor necrosis factor alpha (TNFalpha) is involved in fumonisin-induced hepatotoxic effects in mice. The hepatic response to fumonisin B(1) (FB(1)) was reduced in transgenic animals lacking either of the two TNFalpha receptors. In the present study, we hypothesized that the effect of a similar fumonisin treatment in animals lacking either TNFalpha or both TNFalpha receptors would be considerably less than their wild type (WT) counterparts. The FB(1)-induced increase in circulating liver enzymes was enhanced by deletion of TNFalpha or unchanged in mice lacking both TNFalpha receptors. These findings corresponded with the degree of toxicity as established by microscopic examination of liver. FB(1) induced the expression of TNFalpha in the liver of all strains, except the animals with a deleted TNFalpha gene. The FB(1)-mediated increases in liver sphingosine or sphinganine paralleled the hepatotoxic responses. It is apparent that the presence of TNFalpha is not necessary for FB(1)-induced hepatotoxicity in mice and a lack of the function of this cytokine may aggravate the hepatotoxic responses to fumonisins, perhaps by preventing repair mechanisms or by expression of other signaling molecules. These observations were in accordance with our previous finding where over-expression of TNFalpha also protected against FB(1)-mediated hepatotoxicity, and with the reported beneficial functions of low-level TNFalpha in tissue regeneration.
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Affiliation(s)
- Raghubir P Sharma
- Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA.
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Leonis MA, Toney-Earley K, Degen SJF, Waltz SE. Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure. Hepatology 2002; 36:1053-60. [PMID: 12395314 DOI: 10.1053/jhep.2002.36822] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
The targeted deletion of the cytoplasmic domain of the Ron receptor tyrosine kinase (TK) in mice leads to exaggerated responses to injury in several murine models of inflammation as well as increased lethality in response to endotoxin (lipopolysaccharide [LPS]). Using a well-characterized model of LPS-induced acute liver failure (ALF) in galactosamine (GalN)-sensitized mice, we show that Ron TK(-/-) mice display marked protection compared with control Ron TK(+/+) mice. Whereas control mice have profound elevation of serum aminotransferase levels (a marker of hepatocyte injury) and hemorrhagic necrosis of the liver, in dramatic contrast, Ron TK(-/-) mice have mild elevation of aminotransferase levels and relatively normal liver histology. These findings are associated with a reduction in the number of liver cells undergoing apoptosis in Ron TK(-/-) mice. Paradoxically, treatment of Ron TK(-/-) mice with LPS/GalN leads to markedly elevated (3.5-fold) serum levels of tumor necrosis factor (TNF) alpha, a key inflammatory mediator in this liver injury model, as well as reduced amounts of interleukin (IL) 10 (a suppressor of TNF-alpha production) and interferon (IFN)-gamma (a TNF-alpha sensitizer). These results show that ablation of the TK activity of the Ron receptor leads to protection from the development of hepatocellular apoptosis in response to treatment with LPS/GalN, even in the presence of excessive levels of serum TNF-alpha. In conclusion, our studies show that the Ron receptor TK plays a critical role in modulating the response of the liver to endotoxin.
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Affiliation(s)
- Mike A Leonis
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Research Foundation and Department of Pediatrics, University of Cincinnati, OH 45229, USA
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Leifeld L, Cheng S, Ramakers J, Dumoulin FL, Trautwein C, Sauerbruch T, Spengler U. Imbalanced intrahepatic expression of interleukin 12, interferon gamma, and interleukin 10 in fulminant hepatitis B. Hepatology 2002; 36:1001-8. [PMID: 12297850 DOI: 10.1053/jhep.2002.35532] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In murine models, overexpression of interleukin (IL)-12 and interferon (IFN)-gamma can induce severe liver damage, whereas IL-10 has anti-inflammatory and hepatoprotective properties. To analyze the potential role of these cytokines in human fulminant hepatitis B, we used immunohistochemistry to study expression of IL-12, IFN-gamma, and IL-10 in explant livers of 11 patients with fulminant hepatitis B, 5 patients with fulminant hepatitis due to other etiologies, 37 patients with chronic liver disease (CLD; hepatitis B virus, n = 15; hepatitis C virus, n = 10; primary biliary cirrhosis, n = 12), and 10 normal controls (NCs). Furthermore, cytokine messenger RNA (mRNA) levels were determined in the liver specimens by quantitative real-time polymerase chain reaction (PCR). In NCs, faint IL-12 expression was detected in only a few Kupffer cells, whereas sinusoidal endothelial cells, hepatic stellate cells, bile ducts, and lymphocytes expressed IL-12 in CLD and, more conspicuously, in fulminant hepatitis B. In contrast, expression of IFN-gamma and IL-10 was restricted to lymphocytes and Kupffer cells, respectively. In fulminant hepatitis B, numbers of IL-12- and IFN-gamma-positive cells markedly exceeded those found in CLD and NCs. A close correlation existed between IL-12 and IFN-gamma expression (r = 0.68; P <.001). In contrast, IL-10 expression was not significantly different in CLD and fulminant hepatitis. The quantitative differences in immunohistologic cytokine expression closely corresponded to the mRNA levels. In conclusion, our data indicate massive induction of the proinflammatory cytokines IL-12 and IFN-gamma in fulminant hepatitis B, which is apparently not counterbalanced by the anti-inflammatory cytokine IL-10. This cytokine imbalance may play an important role in promoting inflammatory reactions leading to massive liver damage in fulminant hepatitis B.
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Affiliation(s)
- Ludger Leifeld
- Department of Internal Medicine I, University of Bonn, Germany.
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Bhandari N, Brown CC, Sharma RP. Fumonisin B1-induced localized activation of cytokine network in mouse liver. Food Chem Toxicol 2002; 40:1483-91. [PMID: 12387313 DOI: 10.1016/s0278-6915(02)00075-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Fumonisin B1 (FB1), a mycotoxin produced primarily by Fusarium veticillioides and related fungi, is a carcinogen and causative agent of various animal diseases. Our previous studies indicated the involvement of tumor necrosis factor-alpha (TNFalpha) in FB1-induced hepatotoxicity. Male B6,129 mice (five/group) were injected subcutaneously with vehicle or 2.25 mg/kg/day of FB1 for 5 days and sampled 1 day after the last treatment. FB1 treatment caused an increased expression of TNFalpha, interferon gamma (IFNgamma) and interleukin (IL)-12 p40 in liver without any changes in kidney or spleen, suggesting the localized site of their production. IL-1beta cytokine expression was increased in liver and kidney after FB1 exposure. Cells involved in TNFalpha production after FB1 treatment in liver were identified as Kupffer cells. FB1 increased alanine aminotransferase in plasma and increased apoptotic cells in liver. Selective increase in proinflammatory T helper (Th)1-cytokines (IL-12 and IFNgamma) and TNFalpha with no alteration in Th2-cytokines (IL-4, IL-6 and IL-10) suggest the involvement of IL-12, produced by Kupffer cells, in induction of IFNgamma production by natural killer (NK) cells and/or NK1+ T cells, which can undergo a positive amplification loop with TNFalpha produced by macrophages or other hepatic cells to elicit the toxic reaction.
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Affiliation(s)
- N Bhandari
- Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens 30602, USA
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Abstract
Nonalcoholic steatohepatitis (NASH) is a metabolic disorder of the liver, which, although usually relatively mild, may in some cause fibrosis, cirrhosis, and premature death resulting from liver failure. Its prevalence is increasing, and it is probably underestimated as a cause for cirrhosis. The need for an effective treatment is clear and urgent. Although several small, pilot, and randomized studies have been reported, large-scale studies are yet to be performed in patients with NASH. The aim of therapy is to intervene early in patients at risk of progression of liver disease. In this review, we summarize the extant literature on the management of NASH and discuss the potential future therapies and prophylactic recommendations in patients with NASH.
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Affiliation(s)
- Sanjay Agrawal
- Department of Medicine, The Liver-Biliary-Pancreatic Center of the University of Massachusetts Medical School, Worchester, USA
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Ryll R, Kumazawa Y, Yano I. Immunological properties of trehalose dimycolate (cord factor) and other mycolic acid-containing glycolipids--a review. Microbiol Immunol 2002; 45:801-11. [PMID: 11838897 DOI: 10.1111/j.1348-0421.2001.tb01319.x] [Citation(s) in RCA: 123] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Mycolic acids are characteristic fatty acids of Mycobacteria and are responsible for the wax-like consistence of these microorganisms. Decades of research revealed that mycolic acid-containing glycolipids, in particular trehalose-6,6'-dimycolate (TDM, cord factor) as their best-studied representative, exert a number of immunomodifying effects. They are able to stimulate innate, early adaptive and both humoral and cellular adaptive immunity. Most functions can be associated with their ability to induce a wide range of chemokines (MCP-1, MIP-1alpha, IL-8) and cytokines (e.g., IL-12, IFN-gamma, TNF-alpha, IL-4, IL-6, IL-10). This review tries to link well-known properties of mycolic acid-containing glycolipids, e.g., stimulation of cellular and humoral immunity, granuloma formation and anti-tumor activity, with recent findings in molecular immunology and to give an outlook on potential practical applications.
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Affiliation(s)
- R Ryll
- Japan BCG Laboratory, Kiyose, Tokyo.
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Kobayashi T, Song QH, Hong T, Kitamura H, Cyong JC. Preventative effects of the flowers of Inula britannica on autoimmune diabetes in C57BL/KsJ mice induced by multiple low doses of streptozotocin. Phytother Res 2002; 16:377-82. [PMID: 12112297 DOI: 10.1002/ptr.868] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
We have reported that an aqueous extract from the flowers of Inula britannica L. subsp. japonica Kitam. (IB) prevented immunologically induced experimental hepatitis in mice and suggested that the antihepatitic effect of IB is due to inhibition of IFN-gamma production. We then investigated the effects of IB on diabetes in mice induced by multiple low doses of streptozotocin (MLDSTZ), which is a mouse model for IFN-gamma-dependent autoimmune diabetes. C57BL/KsJ mice (male, 7 weeks) were provided with IB extract (500 mg/ kg/ day) in drinking water ad libitum, starting 7 days before the first STZ injection. Autoimmune diabetes was induced by MLDSTZ (40 mg/kg/day for 5 daily doses, i.p.). The IB treatment significantly suppressed the increase of blood glucose levels. Histological analysis of the pancreas showed that the degree of insulitis and destruction of beta-cells were reduced by IB treatment. The IFN-gamma production from stimulated splenic T lymphocytes was inhibited by the IB treatment. Moreover, the proportion of IFN-gamma-producing cells in the CD4(+) population, which was increased by MLDSTZ, was significantly decreased by the IB treatment. These results suggest that IB has a preventative effect on autoimmune diabetes by regulating cytokine production.
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MESH Headings
- Animals
- Blood Glucose/drug effects
- Body Weight/drug effects
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/immunology
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Experimental/prevention & control
- Diabetes Mellitus, Type 1/chemically induced
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/pathology
- Diabetes Mellitus, Type 1/prevention & control
- Disease Models, Animal
- Drug Administration Schedule
- Hypoglycemic Agents/pharmacology
- Interferon-gamma/biosynthesis
- Interleukin-4/biosynthesis
- Inula/chemistry
- Islets of Langerhans/drug effects
- Islets of Langerhans/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Phytotherapy
- Plant Extracts/chemistry
- Plant Extracts/pharmacology
- Plant Structures/chemistry
- Streptozocin/administration & dosage
- Streptozocin/pharmacology
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Affiliation(s)
- Takao Kobayashi
- Department of Bioregulatory Function, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyou-ku, Tokyo 113-8655, Japan.
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Louis H, Le Moine A, Flamand V, Nagy N, Quertinmont E, Paulart F, Abramowicz D, Le Moine O, Goldman M, Devière J. Critical role of interleukin 5 and eosinophils in concanavalin A-induced hepatitis in mice. Gastroenterology 2002; 122:2001-10. [PMID: 12055605 DOI: 10.1053/gast.2002.33620] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND & AIMS Eosinophils are observed in several liver diseases, but their contribution in the pathogenesis of these disorders remains poorly investigated. Concanavalin A (Con A)-induced hepatitis is an experimental model of immune-mediated liver injury in which natural killer T (NKT) cells play a critical role through the production of interleukin (IL)-4 and the expression of Fas ligand (FasL). Because activated NKT cells also produce IL-5, a critical cytokine for eosinophil maturation and function, the role of IL-5 was investigated in this model. METHODS IL-5-deficient mice, eosinophil depletion in wild-type (WT) mice, and NKT cell transfer from WT- or IL-5-deficient mice into NKT cell-deficient mice were used to assess the role of IL-5 and eosinophils. RESULTS Liver eosinophil infiltrate and IL-5 production were observed after Con A challenge. Liver injury was dramatically reduced in IL-5-deficient or eosinophil-depleted mice. In addition, residual hepatitis observed in Fas-deficient mice was abolished after IL-5 neutralization. Finally, we showed that NKT cells constituted a critical source of IL-5. Indeed, transfer of WT NKT cells to mice lacking NKT cells restored liver injury, whereas transfer of IL-5-deficient NKT cells did not. CONCLUSIONS These observations highlight the pathologic role of IL-5 and eosinophils in experimental immune-mediated hepatitis.
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Affiliation(s)
- Hubert Louis
- Laboratory of Experimental Gastroenterology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
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Shimizu Y, Margenthaler JA, Landeros K, Otomo N, Doherty G, Flye MW. The resistance of P. acnes--primed interferon gamma-deficient mice to low-dose lipopolysaccharide-induced acute liver injury. Hepatology 2002; 35:805-14. [PMID: 11915026 DOI: 10.1053/jhep.2002.32484] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Endotoxin has been identified as a principal mediator of sepsis, often with resulting multiple organ failure. Although interferon gamma (IFN-gamma) has a central role in controlling bacterial infection through the activation of macrophages and T lymphocytes, it can also enhance the harmful effects of the inflammatory response. To examine the role of IFN-gamma in lipopolysaccharide (LPS)-induced injury, we administered LPS (20 or 800 microg/mouse) alone or as low-dose LPS (20 microg/mouse) 7 days after heat-killed Propionibacterium acnes (P. acnes) injection into wild-type C57BL/6 (B6) mice or IFN-gamma-deficient (GKO) mice (B6 background). Although low-dose (20 microg) LPS alone had no effect on survival, the administration of 800 microg LPS alone resulted in 100% mortality in both B6 and GKO mice without significant hepatic mononuclear cellular infiltration or differences in elevated plasma tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and IL-12 levels. In contrast, mortality after low-dose (20 microg) LPS challenge in P. acnes-primed B6 mice was 100%, but 0% in GKO mice. In vivo plasma cytokine (IFN-gamma, TNF-alpha, IL-6, and IL-12) levels and in vitro cytokine production by hepatic mononuclear cells were significantly higher in B6 mice compared with GKO mice. Associated hepatic mononuclear cellular infiltration, multifocal liver necrosis, hepatomegaly, and splenomegaly were found in B6 mice, but not in GKO mice. Finally, the anti-inflammatory NK1.1+CD4+ cell proportion of hepatic infiltrating mononuclear cell numbers 7 days after P. acnes administration was significantly reduced in B6 compared with GKO mice, whereas the proportion of inflammatory NK1.1+CD4- cells was increased. In conclusion, these data suggest that IFN-gamma mediates P. acnes-primed low-dose LPS injury through the hepatic infiltration of mononuclear cells and the subsequent elevation of inflammatory cytokines after LPS challenge, whereas the lethal effects of high-dose LPS alone does not depend on the presence of IFN-gamma.
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Affiliation(s)
- Yoshiaki Shimizu
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
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