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Qin J, Zhu W, Zhou W. Navigating the Paradox of IL-22: Friend or Foe in Hepatic Health? J Gastroenterol Hepatol 2025. [PMID: 40358483 DOI: 10.1111/jgh.16991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 03/11/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025]
Abstract
Interleukin-22 (IL-22), a cytokine from the IL-10 family produced by T cells and innate lymphoid cells, plays a crucial role in immune responses and tissue regeneration. Its association with liver disease has garnered significant attention; however, its exact impact remains controversial. This review aims to enhance the current understanding of the dual role of IL-22 in liver disease by exploring its protective and pathogenic effects. First, we provide an overview of IL-22 biology, including its source, receptors, and signaling pathways. Subsequently, we offer a comprehensive overview of the dual function of IL-22 in non-neoplastic liver disease, emphasizing its antiapoptotic and regenerative properties. We also discuss the applicability of the conclusions drawn from studies on nonalcoholic fatty liver disease to metabolic dysfunction-associated steatotic liver disease. Furthermore, we elaborate on the intricate role of IL-22 in hepatocellular carcinoma, particularly its influence on the tumor microenvironment, proliferation, and immune evasion. In conclusion, IL-22 is paradoxical in liver disease, acting as a friend and foe. It is imperative to understand this paradox to develop targeted therapies that capitalize on the beneficial effects of IL-22 while mitigating its detrimental effects.
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Affiliation(s)
- Jianqi Qin
- The Second Hospital of Lanzhou University, Department of General Surgery, Lanzhou University Second Clinical Medical College; Key Laboratory of Environmental Oncology of Gansu Province, Lanzhou, Gansu, China
| | - Weixiong Zhu
- The Second Hospital of Lanzhou University, Department of General Surgery, Lanzhou University Second Clinical Medical College; Key Laboratory of Environmental Oncology of Gansu Province, Lanzhou, Gansu, China
| | - Wence Zhou
- The Second Hospital of Lanzhou University, Department of General Surgery, Lanzhou University Second Clinical Medical College; Key Laboratory of Environmental Oncology of Gansu Province, Lanzhou, Gansu, China
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2
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Fu L, Yokus B, Gao B, Pacher P. An Update on IL-22 Therapies in Alcohol-Associated Liver Disease and Beyond. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00117-8. [PMID: 40254130 DOI: 10.1016/j.ajpath.2025.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/14/2025] [Accepted: 03/21/2025] [Indexed: 04/22/2025]
Abstract
Excessive alcohol consumption drives the development of alcohol-associated liver disease (ALD), including steatohepatitis, cirrhosis, and hepatocellular carcinoma, and its associated complications, such as hepatorenal syndrome. Hepatocyte death, inflammation, and impaired liver regeneration are key processes implicated in the pathogenesis and progression of ALD. Despite extensive research, therapeutic options for ALD remain limited. IL-22 has emerged as a promising therapeutic target because of its hepatoprotective properties mediated through the activation of the STAT3 signaling pathway. IL-22 enhances hepatocyte survival by mitigating apoptosis, oxidative stress, and inflammation while simultaneously promoting liver regeneration through the proliferation of hepatocytes and hepatic progenitor cells and the up-regulation of growth factors. Additionally, IL-22 exerts protective effects on epithelial cells in various organs affected by ALD and its associated complications. Studies from preclinical models and early-phase clinical trials of IL-22 agonists, such as F-652 and UTTR1147A, have shown favorable safety profiles, good tolerability, and encouraging efficacy in reducing liver injury and promoting regeneration. However, the heterogeneity and multifactorial nature of ALD present ongoing challenges. Further research is needed to optimize IL-22-based therapies and clarify their roles within a comprehensive approach to ALD management. This review summarizes the current understanding of IL-22 biology and its role in ALD pathophysiology and ALD-associated complications along with therapeutic application of IL-22, potential benefits, and limitations.
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Affiliation(s)
- Lihong Fu
- Laboratory of Cardiovascular Physiology and Tissue Injury, NIH/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
| | - Burhan Yokus
- Laboratory of Cardiovascular Physiology and Tissue Injury, NIH/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
| | - Bin Gao
- Laboratory of Liver Diseases, NIH/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, NIH/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
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Morrison MA, Artru F, Trovato FM, Triantafyllou E, McPhail MJ. Potential therapies for acute-on-chronic liver failure. Liver Int 2025; 45:e15545. [PMID: 36800487 PMCID: PMC11815631 DOI: 10.1111/liv.15545] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 01/16/2023] [Accepted: 02/15/2023] [Indexed: 02/19/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome that develops in approximately 30% of patients hospitalised with cirrhosis and is characterised by an acute decompensation of liver function associated with extra-hepatic organ failures and a high short-term mortality. At present, no specific therapies are available for ACLF, and current management is limited to treatment of the precipitating event and organ support. Given the high prevalence and high mortality of this severe liver disease, there is an urgent need for targeted treatments. There is increasing evidence of the important role played by systemic inflammation and immune dysfunction in the pathophysiology of ACLF and a better understanding of these immune processes is resulting in new therapeutic targets. The aim of this review is to present an overview of ongoing studies of potentially promising therapies and how they could be utilised in the management of ACLF.
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Affiliation(s)
- Maura A. Morrison
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
| | - Florent Artru
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
| | - Francesca M. Trovato
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
| | - Evangelos Triantafyllou
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
| | - Mark J. McPhail
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
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Hwang S, Hicks A, Hoo CZ, Kwon YS, Cho YE, Moore J, Gao B. Novel treatment of acute and acute-on-chronic liver failure: Interleukin-22. Liver Int 2025; 45:e15619. [PMID: 37208937 PMCID: PMC10657333 DOI: 10.1111/liv.15619] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/15/2023] [Accepted: 05/09/2023] [Indexed: 05/21/2023]
Abstract
Acute liver failure (ALF) is a life-threatening medical condition, characterized by rapidly progressive hepatic dysfunction, coagulopathy and hepatic encephalopathy in patients without chronic liver disease, while acute-on-chronic liver failure (ACLF) occurs in patients with existing chronic liver disease. ALF and ACLF are often associated with multiple organ failure and a high short-term mortality. In this review, we briefly discuss the causes and pathogenesis of ALF and ACLF, the current options available for the treatment of both deadly maladies and interleukin-22 (IL-22), a novel promising drug that may have great therapeutic potential for ALF and ACLF treatment. IL-22 is a cytokine produced by immune cells but mainly targets epithelial cells including hepatocytes. IL-22 has been shown to protect against organ damage and reduce bacterial infection in many preclinical models and several clinical trials including alcohol-associated hepatitis. The potential application of IL-22 for the treatment of ALF and ACLF is also elaborated.
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Affiliation(s)
- Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Amy Hicks
- Leeds Liver Unit, St James’s University Hospital, UK
| | - Chai Zhen Hoo
- Leeds Liver Unit, St James’s University Hospital, UK
| | - Yong Seong Kwon
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Ye Eun Cho
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Joanna Moore
- Leeds Liver Unit, St James’s University Hospital, UK
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
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5
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Lin Y, Yan GJ, Liu MY, Cao Y, Zhang K, Wang N, Long FL, Mao DW. Review of the potential value of serum interleukin levels as prognostic biomarkers of liver failure. World J Clin Cases 2024; 12:6045-6056. [PMID: 39328855 PMCID: PMC11326103 DOI: 10.12998/wjcc.v12.i27.6045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 07/03/2024] [Accepted: 07/10/2024] [Indexed: 07/29/2024] Open
Abstract
Liver failure (LF) is prevalent in China and is characterized by complex pathogenesis, challenging clinical management, poor prognosis, and rising incidence and mortality rates. The immune status is an important factor affecting LF prognosis. Interleukins (Ils) are a type of cytokine that act and interact with multiple cells, including immune cells. These signaling molecules play important roles in intercellular information transmission, including the regulation of immune cells; mediation of the activation, proliferation, and differentiation of T and B cells; and orchestration of the inflammatory response. To date, many studies have explored the correlation between IL expression and liver disease prognosis, but few studies have evaluated Ils as the prognostic biomarkers of LF. This article reviews the potential use of Ils as the prognostic biomarkers of LF. Particularly, it evaluates the predictive values of IL-21, IL-22, and IL-31, the three often overlooked yet promising prognostic biomarkers, in predicting susceptibility to LF. Harnessing biomarkers for early prognostic insights can facilitate tailored treatment strategies and enhance patient survival. Thus, this article focuses on the identification of IL-21, IL-22, and IL-33 as biomarkers in preclinical and clinical studies on LF and reviews their role as biomarkers in the pathogenesis and diagnosis of LF.
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Affiliation(s)
- Yong Lin
- Graduate School, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
| | - Geng-Jie Yan
- Graduate School, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
| | - Mei-Yan Liu
- Graduate School, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
| | - Yin Cao
- Guangxi School of Chinese Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Kan Zhang
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Na Wang
- Department of Administration, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Fu-Li Long
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - De-Wen Mao
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
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Abdelnabi MN, Hassan GS, Shoukry NH. Role of the type 3 cytokines IL-17 and IL-22 in modulating metabolic dysfunction-associated steatotic liver disease. Front Immunol 2024; 15:1437046. [PMID: 39156888 PMCID: PMC11327067 DOI: 10.3389/fimmu.2024.1437046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 07/12/2024] [Indexed: 08/20/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits.
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Affiliation(s)
- Mohamed N. Abdelnabi
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Ghada S. Hassan
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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Zhou H, Xu JL, Huang SX, He Y, He XW, Lu S, Yao B. Hepatic vagotomy blunts liver regeneration after hepatectomy by downregulating the expression of interleukin-22. World J Gastrointest Surg 2023; 15:2866-2878. [PMID: 38222006 PMCID: PMC10784834 DOI: 10.4240/wjgs.v15.i12.2866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/01/2023] [Accepted: 11/17/2023] [Indexed: 12/27/2023] Open
Abstract
BACKGROUND Rapid regeneration of the residual liver is one of the key determinants of successful partial hepatectomy (PHx). At present, there is a lack of recognized safe, effective, and stable drugs to promote liver regeneration. It has been reported that vagus nerve signaling is beneficial to liver regeneration, but the potential mechanism at play here is not fully understood. AIM To explore the effect and mechanism of hepatic vagus nerve in liver regeneration after PHx. METHODS A PHx plus hepatic vagotomy (Hv) mouse model was established. The effect of Hv on liver regeneration after PHx was determined by comparing the liver regeneration levels of the PHx-Hv group and the PHx-sham group mice. In order to further investigate the role of interleukin (IL)-22 in liver regeneration inhibition mediated by Hv, the levels of IL-22 in the PHx-Hv group and the PHx-sham group was measured. The degree of liver injury in the PHx-Hv group and the PHx-sham group mice was detected to determine the role of the hepatic vagus nerve in liver injury after PHx. RESULTS Compared to control-group mice, Hv mice showed severe liver injury and weakened liver regeneration after PHx. Further research found that Hv downregulates the production of IL-22 induced by PHx and blocks activation of the signal transducer and activator of transcription 3 (STAT3) pathway then reduces the expression of various mitogenic and anti-apoptotic proteins after PHx. Exogenous IL-22 reverses the inhibition of liver regeneration induced by Hv and alleviates liver injury, while treatment with IL-22 binding protein (an inhibitor of IL-22 signaling) reduce the concentration of IL-22 induced by PHx, inhibits the activation of the STAT3 signaling pathway in the liver after PHx, thereby hindering liver regeneration and aggravating liver injury in PHx-sham mice. CONCLUSION Hv attenuates liver regeneration after hepatectomy, and the mechanism may be related to the fact that Hv downregulates the production of IL-22, then blocks activation of the STAT3 pathway.
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Affiliation(s)
- Heng Zhou
- Department of Pharmacy, The First People’s Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, Zhejiang Province, China
| | - Ju-Ling Xu
- Department of Medicine, Medical School of Huzhou University, Huzhou 313000, Zhejiang Province, China
| | - San-Xiong Huang
- Department of Hepatobiliary Surgery, The First People’s Hospital of Huzhou, Huzhou 313000, Zhejiang Province, China
| | - Ying He
- Zhejiang Provincial Key Laboratory of Media Biology and Pathogenic Control, Central Laboratory, First Affiliated Hospital of Huzhou University, Huzhou 313000, Zhejiang Province, China
| | - Xiao-Wei He
- Department of Pharmacy, The First People’s Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, Zhejiang Province, China
| | - Sheng Lu
- Department of Pharmacy, The First People’s Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, Zhejiang Province, China
| | - Bin Yao
- Department of Pharmacy, The First People’s Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, Zhejiang Province, China
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8
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Sagaram M, Frimodig J, Jayanty D, Hu H, Royer AJ, Bruner R, Kong M, Schwandt ML, Vatsalya V. One-month assessment of Th-cell axis related inflammatory cytokines, IL-17 and IL-22 and their role in alcohol-associated liver disease. Front Immunol 2023; 14:1202267. [PMID: 38162671 PMCID: PMC10755956 DOI: 10.3389/fimmu.2023.1202267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 11/30/2023] [Indexed: 01/03/2024] Open
Abstract
Introduction Changes in the expression of cyto- and chemokines due to alcohol-associated liver disease (ALD) have been reported to be both protective and pathogenic. This study examined plasma levels of two key cytokines, Il-17 and Il-22, which construct the proinflammatory vs. anti-inflammatory axes across the spectrum of alcohol use disorder (AUD) and ALD including alcohol-associated hepatitis (AH) to determine the underlying status of the inflammation. Methods Forty-two males and females aged 25-63 yrs. were grouped as healthy controls (HV[n=8]), AUD with no liver injury (AUDNLI [n=8]), AUD with liver injury (AUDLI [n=8]), non-severe alcohol-associated hepatitis (NSAH [n=9]), and severe alcohol-associated hepatitis (SAH [n=9]). Demographic, drinking, and clinical data were collected. Blood samples were collected at baseline (BL, all subjects) and during week 4 (W4, only patients) for IL-17 and IL-22; and statistically analyzed. Results IL-17 was highly elevated in the SAH group both at BL and post-SOC. LTDH and BL IL-22 in non-severe AH patients were associated significantly. LTDH significantly predicted W4 IL-22 levels, positively (increasing) in NSAH and inversely (lowering) in SAH patients. BL and W4 IL-22 levels were significantly higher (4-fold, p≤0.001) in all AH patients compared to all AUD patients (AUROC=0.988, p≤0.001). IL-22 showed significant affinity with AST, AST: ALT ratio, total bilirubin, INR, and PT both at BL and W4. IL-22 was inversely associated with IL-1β; and positively with TNF-α and IL-8 both at BL, and W4. BL IL-17 showed a positive correlation with MELD (p=0.017) in all AH patients. In SAH, > 2-fold W4 IL-17 level compared to BL showed significant within subjects' effects, p=0.006. In AUD patients without AH, the drop in IL-17 at W4 vs. BL showed a significant within subjects' effect, p=0.031. Discussion Drinking chronicity predicted opposite effects in IL-22 levels in NSAH (antiinflammatory) and SAH (pro-inflammatory) patients at post-SOC. BL IL-22 levels differentiated AH patients robustly from the AUD patients (with or without liver injury); and showed corresponding increases stepwise with the stages of ALD. IL-22 was closely associated with progression and injury markers of the liver; and response to the cytokines of pro-inflammatory nature. Pro-inflammatory indicator of IL-17 cell axis, IL-17 showed a strong positive association with MELD, a severity indicator of AH.
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Affiliation(s)
- Manasa Sagaram
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Department of Medicine, Robley Rex VA Medical Center, Louisville, KY, United States
- Clinical Laboratory for Intervention Development of AUD and Organ Severity, Louisville, KY, United States
| | - Jane Frimodig
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Department of Medicine, Robley Rex VA Medical Center, Louisville, KY, United States
| | - Danielle Jayanty
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Clinical Laboratory for Intervention Development of AUD and Organ Severity, Louisville, KY, United States
| | - Huirong Hu
- Clinical Laboratory for Intervention Development of AUD and Organ Severity, Louisville, KY, United States
- School of Public Health and Information Sciences, University of Louisville, Louisville, KY, United States
| | - Amor J. Royer
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Clinical Laboratory for Intervention Development of AUD and Organ Severity, Louisville, KY, United States
| | - Ryne Bruner
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Clinical Laboratory for Intervention Development of AUD and Organ Severity, Louisville, KY, United States
| | - Maiying Kong
- School of Public Health and Information Sciences, University of Louisville, Louisville, KY, United States
- Department of Medicine, University of Louisville Alcohol Research Center, Louisville, KY, United States
| | - Melanie L. Schwandt
- Division of Intramural Clinical and Biological Research (DICBR) National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, United States
| | - Vatsalya Vatsalya
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Department of Medicine, Robley Rex VA Medical Center, Louisville, KY, United States
- Clinical Laboratory for Intervention Development of AUD and Organ Severity, Louisville, KY, United States
- Department of Medicine, University of Louisville Alcohol Research Center, Louisville, KY, United States
- Division of Intramural Clinical and Biological Research (DICBR) National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, United States
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9
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Juanola A, Ma AT, de Wit K, Gananandan K, Roux O, Zaccherini G, Jiménez C, Tonon M, Solé C, Villaseca C, Uschner FE, Graupera I, Pose E, Moreta MJ, Campion D, Beuers U, Mookerjee RP, Francoz C, Durand F, Vargas V, Piano S, Alonso S, Trebicka J, Laleman W, Asrani SK, Soriano G, Alessandria C, Serra-Burriel M, Morales-Ruiz M, Torres F, Allegretti AS, Krag A, Caraceni P, Watson H, Abraldes JG, Solà E, Kamath PS, Hernaez R, Ginès P. Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis. Gut 2023; 73:156-165. [PMID: 37884354 DOI: 10.1136/gutjnl-2023-329923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 09/18/2023] [Indexed: 10/28/2023]
Abstract
BACKGROUND Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications. METHODS We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not. RESULTS Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46). CONCLUSION Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.
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Affiliation(s)
- Adrià Juanola
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
| | - Ann Thu Ma
- Toronto Centre for Liver Disease Francis Family Liver Clinic, Toronto General Hospital, Toronto, Ontario, Canada
| | - Koos de Wit
- Gastroenterology and Hepatology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands
| | - Kohilan Gananandan
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Olivier Roux
- Department of Hepatology, Beaujon Hospital, Clichy, France
| | - Giacomo Zaccherini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-related Diseases, University of Bologna Hospital of Bologna Sant'Orsola-Malpighi Polyclinic, Bologna, Italy
| | - César Jiménez
- Liver Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain
| | - Marta Tonon
- Department of Medicine (DIMED), University of Padova, Padova, Italy
| | - Cristina Solé
- Department of Gastroenterology and Hepatology, Consorci Corporació Sanitària Parc Taulí, Sabadell, Spain
| | - Clara Villaseca
- Digestive Disease Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Frank E Uschner
- Department of Internal Medicine B, University of Münster, Munster, Germany
| | - Isabel Graupera
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
| | - Elisa Pose
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
| | - Maria José Moreta
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
| | - Daniela Campion
- Division of Gastroenterology and Hepatology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Ulrich Beuers
- Gastroenterology & Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Rajeshawar P Mookerjee
- Institute of Liver and Digestive Health, University College London Medical School, London, UK
| | - Claire Francoz
- Department of Hepatology, Beaujon Hospital, Clichy, France
| | - Francois Durand
- DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France
- Université Denis Diderot-Paris 7, Paris, France
| | - Victor Vargas
- Liver Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain
| | - Salvatore Piano
- Department of Medicine (DIMED), University of Padova, Padova, Italy
| | - Sonia Alonso
- Digestive Disease Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Munster, Germany
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Wim Laleman
- Division of Liver and Biliopanreatic Disorders, KU Leuven, University of Leuven, Leuven, Belgium
| | - Sumeet K Asrani
- Division of Hepatology, Department of Medicine, Baylor University Medical Center at Dallas, Dallas, Texas, USA
| | - German Soriano
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Miquel Serra-Burriel
- University of Zurich Institute of Epidemiology Biostatistics and Prevention, Zurich, Switzerland
| | - Manuel Morales-Ruiz
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Ferran Torres
- Biostatistics and Data Management Core Facility, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Andrew S Allegretti
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Aleksander Krag
- Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Juan G Abraldes
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Alberta, Canada
| | - Elsa Solà
- Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, California, USA
| | - Patrick S Kamath
- Gastroenterology and Hepatology, Mayo Medical School, Rochester, Minnesota, USA
| | - Ruben Hernaez
- Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
- Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Pere Ginès
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
- Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain
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Dimitriadis K, Katelani S, Pappa M, Fragkoulis GE, Androutsakos T. The Role of Interleukins in HBV Infection: A Narrative Review. J Pers Med 2023; 13:1675. [PMID: 38138902 PMCID: PMC10744424 DOI: 10.3390/jpm13121675] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/17/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a worldwide medical issue with significant morbidity and mortality, as it is the main cause of chronic liver disease and hepatocellular carcinoma (HCC). Both innate and adaptive immune responses play a key role in HBV replication and suppression. Recently, the pathophysiological function of interleukins (IL) in the natural course of HBV has gained much attention as a result of the broad use of anti-interleukin agents for a variety of autoimmune diseases and the accompanying risk of HBV reactivation. We present a narrative review regarding the role of IL in HBV infection. Collectively, the pro-inflammatory ILs, namely IL-1, IL-5, IL-6, IL-12 and IL-21, seem to play a critical role in the suppression of HBV replication. In contrast, the anti-inflammatory cytokines IL-10, IL-23 and IL-35 probably act as HBV replication enhancers, while IL-17 has been correlated with HBV-related liver injury. Interestingly enough, IL-2, IL-4 and IL-12 have been tried as therapeutic options against HBV infection with contradictory results. Lastly, the role of IL-22 remains largely ill defined, although preliminary data suggest that it may play a significant role in HBV replication, proliferation and subsequent liver damage.
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Affiliation(s)
- Konstantinos Dimitriadis
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.D.); (S.K.)
| | - Stamatia Katelani
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.D.); (S.K.)
| | - Maria Pappa
- First Department of Internal Medicine, Propaedeutic Clinic, “Laiko” Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.P.); (G.E.F.)
| | - George E. Fragkoulis
- First Department of Internal Medicine, Propaedeutic Clinic, “Laiko” Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.P.); (G.E.F.)
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8QQ, UK
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.D.); (S.K.)
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11
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Konstantis G, Tsaousi G, Pourzitaki C, Kitsikidou E, Magouliotis DE, Wiener S, Zeller AC, Willuweit K, Schmidt HH, Rashidi-Alavijeh J. Efficacy of Granulocyte Colony-Stimulating Factor in Acute on Chronic Liver Failure: A Systematic Review and Survival Meta-Analysis. J Clin Med 2023; 12:6541. [PMID: 37892679 PMCID: PMC10607065 DOI: 10.3390/jcm12206541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/02/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) mostly occurs when there is an acute insult to the liver in patients with pre-existing liver disease, and it is characterized by a high mortality rate. Various therapeutic approaches have been used thus far, with orthotopic liver transplantation being the only definitive cure. Clinical trials and meta-analyses have investigated the use of granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow-derived stem cells. Some studies have suggested that G-CSF may have a significant role in the management and survival of patients with ACLF. However, the results are conflicting, and the efficacy of G-CSF still needs to be confirmed. AIM The aim was to assess the efficacy of G-CSF in patients with ACLF. METHODS Electronic databases were searched until May 2023 for randomized controlled trials investigating the use of G-CSF in adult patients with ACLF. Outcome measures were the effects of G-CSF on overall survival, changes in liver disease severity scores, complications of cirrhosis, other G-CSF-related adverse effects, and all-cause mortality. The study's protocol has been registered with Prospero (CRD42023420273). RESULTS Five double-blind randomized controlled trials involving a total of 421 participants met the inclusion criteria. The use of G-CSF demonstrated a significant effect on overall survival (HR 0.63, 95% CI 0.41 to 0.95, and I2 48%), leading to a decreased mortality (LogOR-0.97, 95% CI -1.57 to -0.37, and I2 37.6%) and improved Model for End-Stage Liver Disease (MELD) scores (SMD -0.87, 95% CI -1.62 to -0.13, and I2 87.3%). There was no correlation between the improvement of the Child-Pugh score and the use of G-CSF(SMD -2.47, 95% CI -5.78 to 0.83, and I2 98.1%). The incidence of complications of cirrhosis did not decrease significantly with G-CSF treatment (rate ratio 0.51, 95% CI 0.26 to 1.01, and I2 90%). A qualitative synthesis showed that the use of G-CSF is safe. CONCLUSIONS The administration of G-CSF has demonstrated a positive impact on overall survival, liver function, and the MELD score. The presence of heterogeneity in the included studies prohibits conclusive recommendations.
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Affiliation(s)
- Georgios Konstantis
- Clinical Pharmacology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Georgia Tsaousi
- Department of Anesthesiology and ICU, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Chryssa Pourzitaki
- Clinical Pharmacology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Elisavet Kitsikidou
- Department of Internal Medicine, Evangelical Hospital Dusseldorf, 40217 Dusseldorf, Germany;
| | | | - Sebastian Wiener
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Amos Cornelius Zeller
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Katharina Willuweit
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Hartmut H. Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Jassin Rashidi-Alavijeh
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
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12
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Wang LY, Yang XY, Wu YP, Fan YC. IL-22-producing CD3 + CD8- T cells increase in immune clearance stage of chronic HBV infection and correlate with the response of Peg-interferon treatment. Clin Immunol 2023; 250:109320. [PMID: 37019423 DOI: 10.1016/j.clim.2023.109320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 03/31/2023] [Indexed: 04/05/2023]
Abstract
Interleukin (IL)-22 regulates host defense. This study investigated the predominant IL-22-producing cell subsets under HBV associated immune stages. We found circulating IL-22-producing CD3 + CD8- T cells were significantly increased in immune active (IA) stage than those in immunotolerant stage, inactive carrier and healthy controls (HCs). The plasma IL-22 level was higher in IA and HBeAg-negative CHB compared to HCs. Importantly, CD3 + CD8- T cells were identified as the predominant source of plasma IL-22 production. Up-regulated IL-22-producing CD3 + CD8- T cells obviously correlated with the grade of intrahepatic inflammation. The proportions of IL-22-producing CD3 + CD8- T cells were significantly down-regulated after 48 weeks of Peg-interferon treatment, and the differences were of great significance in patients with normalize ALT levels at 48 weeks, rather than those with elevated ALT levels. In conclusion, IL-22 might play a proinflammatory function in. chronic HBV infected patients with active inflammation and Peg-interferon treatment could attenuate the degree of liver inflammation through down-regulating IL-22-producing CD3 + CD8- T cells.
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Affiliation(s)
- Li-Yuan Wang
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Xue-Yan Yang
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Yin-Ping Wu
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
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13
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Yu X, Zheng Y, Zeng D, Zhou Y, Sun J, Su M, Zhang H, Zheng M, Huang Z, Lin W, Mao R, Zhang J, Zheng C, Su Z. Decreased frequency of a novel T-lymphocyte subset, CD3 + CD4 - CD7 + CD57 - T cells, in hepatitis B virus-related end-stage liver disease might contribute to disease progression. J Med Virol 2023; 95:e28129. [PMID: 36068190 DOI: 10.1002/jmv.28129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/05/2022] [Accepted: 09/05/2022] [Indexed: 01/11/2023]
Abstract
CD7 and CD57 are related to the differentiation and functional stages of CD8+ T cells. However, the role of their combined presence in CD8+ T cells in patients with chronic hepatitis B virus (HBV) infection, especially those with end-stage liver disease, remains unclear. Blood samples from healthy volunteers and patients with chronic hepatitis B were analyzed via Luminex assay and ELISA to measure plasma cytokine levels. Further, recombinant IL-22 was used to stimulate peripheral blood mononuclear cells from healthy volunteers, and the frequency of CD3+ CD4- CD7+ CD57- T cells and apoptosis rates were investigated via flow cytometry. Patients with end-stage liver disease, particularly those with acute to chronic liver failure, showed decreased CD3+ CD4- CD7+ CD57- T cell frequency. Furthermore, the prevalence of CD3+ CD4- CD7+ CD57- T cells was negatively correlated with disease severity, prognosis, and complications (ascites). We also observed that IL-22 promoted apoptosis and brought about a decrease in the number of CD3+ CD4- CD7+ CD57- T cells in a dose-dependent manner. CD3+ CD4- CD7+ CD57- T cells displayed a B and T lymphocyte attenuator (BTLA)high CD25high CD127high immunosuppressive phenotype and showed low interferon-γ, tumor necrosis factor-α, granzyme A, and perforin expression levels. The present findings will elucidate the pathogenesis of HBV-related end-stage liver disease and aid the identification of novel drug targets.
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Affiliation(s)
- Xueping Yu
- Department of Infectious Diseases, Fujian Medical University Affiliated First Quanzhou Hospital, Quanzhou, China.,Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yijuan Zheng
- Department of Infectious Diseases, Fujian Medical University Affiliated First Quanzhou Hospital, Quanzhou, China
| | - Dawu Zeng
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Department of Liver Center, The First Hospital Affiliated to Fujian Medical University, Fuzhou, China
| | - Yongjun Zhou
- Institute of Bioengineering and Biotechnology, College of Life Sciences and Chemistry, Minnan Science and Technology University, Quanzhou, China
| | - Jian Sun
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Department of Infectious Diseases, The First Hospital Affiliated to Wannan Medical College, Wuhu, China
| | - Milong Su
- Department of Infectious Diseases, Fujian Medical University Affiliated First Quanzhou Hospital, Quanzhou, China
| | - Huatang Zhang
- Department of Infectious Diseases, Fujian Medical University Affiliated First Quanzhou Hospital, Quanzhou, China
| | - Minhui Zheng
- Department of Infectious Diseases, Fujian Medical University Affiliated First Quanzhou Hospital, Quanzhou, China
| | - Zhipeng Huang
- Department of Infectious Diseases, Fujian Medical University Affiliated First Quanzhou Hospital, Quanzhou, China
| | - Wenwu Lin
- Department of Infectious Diseases, Fujian Medical University Affiliated First Quanzhou Hospital, Quanzhou, China
| | - Richeng Mao
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, China.,Department of Infectious Diseases, Jing' An Branch of Huashan Hospital, Fudan University, Shanghai, China
| | - Chunfu Zheng
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Zhijun Su
- Department of Infectious Diseases, Fujian Medical University Affiliated First Quanzhou Hospital, Quanzhou, China
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14
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Serum Interleukins as Potential Prognostic Biomarkers in HBV-Related Acute-on-Chronic Liver Failure. Mediators Inflamm 2022; 2022:7794890. [PMID: 36117587 PMCID: PMC9477565 DOI: 10.1155/2022/7794890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/06/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is relatively common in China and has complex pathogenesis, difficult clinical treatment, and poor prognosis. Immune status is an important factor affecting ACLF prognosis. Interleukins are a family of secreted lymphocyte factors that interact with a host of cell types including immune cells. These signaling molecules play important roles in transmitting information; regulating immune cells; mediating the activation, proliferation, and differentiation of T and B cells; and modulating inflammatory responses. Many studies have investigated the correlation between interleukin expression and the prognosis of HBV-ACLF. This review focuses on the potential use of interleukins as prognostic biomarkers in HBV-ACLF. References were mainly identified through PubMed and CNKI search, including relevant studies published until December 2021. We have summarized reports of several promising diagnostic interleukin biomarkers that predict susceptibility to HBV-ACLF. The use of biomarkers to understand early prognosis can help devise different therapeutic measures and improve patient survival. Ongoing research on prognostic biomarkers of HBV-ACLF is promising, and future preclinical and clinical studies are warranted.
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15
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Weber S, Gerbes AL. Challenges and Future of Drug-Induced Liver Injury Research-Laboratory Tests. Int J Mol Sci 2022; 23:ijms23116049. [PMID: 35682731 PMCID: PMC9181520 DOI: 10.3390/ijms23116049] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/22/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
Drug-induced liver injury (DILI) is a rare but potentially severe adverse drug event, which is also a major cause of study cessation and market withdrawal during drug development. Since no acknowledged diagnostic tests are available, DILI diagnosis poses a major challenge both in clinical practice as well as in pharmacovigilance. Differentiation from other liver diseases and the identification of the causative agent in the case of polymedication are the main issues that clinicians and drug developers face in this regard. Thus, efforts have been made to establish diagnostic testing methods and biomarkers in order to safely diagnose DILI and ensure a distinguishment from alternative liver pathologies. This review provides an overview of the diagnostic methods used in differential diagnosis, especially with regards to autoimmune hepatitis (AIH) and drug-induced autoimmune hepatitis (DI-AIH), in vitro causality methods using individual blood samples, biomarkers for diagnosis and severity prediction, as well as experimental predictive models utilized in pre-clinical settings during drug development regimes.
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16
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Lange CM, Al-Juboori K, Rawitzer J, Moellmann D, Schlattjan M, Guckenbiehl S, Willuweit K, Canbay A, Baba HA. Cirrhosis-Based Acute-on-Chronic Liver Failure Is Marked by Inflammation and Impaired Liver Regeneration Despite Stat3 Activation. GASTRO HEP ADVANCES 2022; 1:520-530. [PMID: 39132076 PMCID: PMC11308700 DOI: 10.1016/j.gastha.2022.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 03/10/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Acute-on-chronic liver failure (ACLF) is associated with excessive systemic inflammation, cell death, and organ failures. Yet, little is known about the hepatic histopathology of ACLF. Here, we assessed the histopathology and regenerative capacity of the liver in ACLF with or without cirrhosis. Methods Liver specimens of patients with compensated cirrhosis (N = 37), acute decompensation (N = 40), and ACLF with (N = 18) or without (N = 10) cirrhosis were assessed for morphological features and the pro-regenerative Stat3 pathway. Results ACLF was associated with high levels of lobular inflammation, tissue necrosis, and apoptosis. In patients with cirrhosis, the percentage of pStat3-positive hepatocytes was increasing with disease severity (3.5%/10.4%/21% for compensated cirrhosis/acute decompensation/cirrhosis-ACLF; P < .001), but lower in noncirrhotic ACLF vs cirrhosis-ACLF (21% vs 13%; P = .02). A distinct pattern of the expression of the proliferation marker Ki-67, a downstream effector marker of pStat3, was observed. Ki-67-positive hepatocytes were more frequent in patients with cirrhosis-ACLF compared to compensated cirrhosis or acute decompensation (4.9% vs 1.3% vs 1.8%; P < .05), but much lower in cirrhosis-ACLF vs noncirrhotic ACLF (4.9% vs 13.5%; P = .01). The ratio of Ki-67-positive to pStat3-positive hepatocytes was lowest in cirrhosis-ACLF and predicted 3-month transplant-free survival accurately (area under the curve = 0.95, P < .00001). Conclusion Our study identifies hepatic inflammation and Stat3 activation as hallmarks of ACLF. In cirrhosis-ACLF, Stat3 activation does not appear to translate in effective liver regeneration, which is distinct from noncirrhotic ACLF.
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Affiliation(s)
- Christian M. Lange
- Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany
- Department of Internal Medicine II, LMU University Hospital, Munich, Germany
| | - Kawther Al-Juboori
- Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany
| | - Josefine Rawitzer
- Institute of Pathology, University Hospital and University of Duisburg-Essen, Essen, Germany
| | - Dorothe Moellmann
- Institute of Pathology, University Hospital and University of Duisburg-Essen, Essen, Germany
| | - Martin Schlattjan
- Institute of Pathology, University Hospital and University of Duisburg-Essen, Essen, Germany
| | - Sabrina Guckenbiehl
- Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany
| | - Katharina Willuweit
- Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus Bochum, Bochum, Germany
| | - Hideo A. Baba
- Institute of Pathology, University Hospital and University of Duisburg-Essen, Essen, Germany
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17
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Wang L, Fan Y. Current Advances of Innate and Adaptive Immunity in Acute-on-Chronic Hepatitis B Liver Failure. INFECTIOUS DISEASES & IMMUNITY 2022; 2:113-121. [DOI: 10.1097/id9.0000000000000051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Indexed: 01/03/2025]
Abstract
Abstract
Acute-on-chronic hepatitis B liver failure (ACHBLF) is a term used to define the acute deterioration of liver function that occurs in patients with chronic hepatitis B virus infection or hepatitis B virus-related liver cirrhosis. The specific pathogenesis of ACHBLF is still not completely understood. Current research has shown that an intense systemic inflammation is involved in the development of acute-on-chronic liver failure (ACLF). Meanwhile, a subsequent immune paresis over the course of ACLF favors the development of infection and sepsis. Deregulation in both the innate and adaptive immunity is the notable feature of ACLF. The dysregulated immune responses play a crucial role in disease progression and potentially drive organ failure and mortality in ACHBLF. In this review, we highlight the current knowledge of innate and adaptive immune cells in ACHBLF.
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Affiliation(s)
- Liyuan Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Yuchen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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18
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de Brito RJVC, do Carmo RF, Silva BMS, Costa ACS, Rocha SWS, Vasconcelos LRS, Pereira LMMB, de Moura PMMF. Liver expression of IL-22, IL-22R1 and IL-22BP in patients with chronic hepatitis C with different fibrosis stages. Cytokine 2022; 150:155784. [PMID: 34920229 DOI: 10.1016/j.cyto.2021.155784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 09/28/2021] [Accepted: 12/06/2021] [Indexed: 12/26/2022]
Abstract
AIMS Liver fibrosis is the result of an exacerbated wound-healing response associated with chronic liver injury. Interleukin-22 (IL-22) plays a key role in liver disease, through either a protective or an adverse role, depending on the context. The relationship between IL-22 and its receptors IL-22R1 and IL-22BP (soluble inhibitor) in liver fibrosis is unknown. In this study, we assessed the presence and quantity of IL-22, IL-22R1, and IL-22BP-producing cells in liver tissues of patients with chronic hepatitis C. METHODS AND RESULTS The number of IL-22-producing cells was significantly higher in stages F1, F2, and F3 when compared to F0 or F4 (p < 0.05). The immunostaining of IL-22R1 decreased as liver fibrosis increased from F1 to F4. On the other hand, the concentration of IL-22BP-producing cells was higher in patients with cirrhosis (F4). Furthermore, the IL-22BP:IL-22 ratio was highest in patients with cirrhosis. CONCLUSIONS Our results suggest that IL-22, IL-22R1 and IL-22BP may be involved in the mechanisms of liver fibrosis in patients with chronic hepatitis C.
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Affiliation(s)
- Rodrigo José Videres Cordeiro de Brito
- Postgraduate program in Health Sciences, University of Pernambuco (UPE), Recife, Pernambuco, Brazil; College of Medicine, Federal University of the São Francisco Valley (UNIVASF), Petrolina, Pernambuco, Brazil
| | - Rodrigo Feliciano do Carmo
- College of Pharmacy, Federal University of the São Francisco Valley (UNIVASF), Petrolina, Pernambuco, Brazil.
| | - Bruna Manuella Souza Silva
- College of Pharmacy, Federal University of the São Francisco Valley (UNIVASF), Petrolina, Pernambuco, Brazil
| | - Ana Clara Santos Costa
- Institute of Biological Sciences, University of Pernambuco (UPE), Recife, Pernambuco, Brazil
| | - Sura Wanessa Santos Rocha
- Postgraduate program in Health Sciences, University of Pernambuco (UPE), Recife, Pernambuco, Brazil; Institute of Biological Sciences, University of Pernambuco (UPE), Recife, Pernambuco, Brazil
| | | | - Leila Maria Moreira Beltrão Pereira
- Postgraduate program in Health Sciences, University of Pernambuco (UPE), Recife, Pernambuco, Brazil; Faculty of Medicine, University of Pernambuco (UPE), Recife, Pernambuco, Brazil; Liver Institute of Pernambuco (IFP), Recife, Pernambuco, Brazil
| | - Patrícia Muniz Mendes Freire de Moura
- Postgraduate program in Health Sciences, University of Pernambuco (UPE), Recife, Pernambuco, Brazil; Institute of Biological Sciences, University of Pernambuco (UPE), Recife, Pernambuco, Brazil
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Lamatsch S, Sittner R, Tacke F, Engelmann C. Novel drug discovery strategies for the treatment of decompensated cirrhosis. Expert Opin Drug Discov 2021; 17:273-282. [PMID: 34971342 DOI: 10.1080/17460441.2022.2020755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Disease progression in cirrhosis leads to decompensation and acute-on-chronic liver failure (ACLF), which is characterized by organ failure and high mortality. Portal hypertension and cardiovascular dysfunction trigger the development of cirrhosis-related complications whilst tissue injury and cellular metabolic dysfunction lead to organ failure. System inflammation is the overarching mechanism mediating both the transition from compensation to decompensation as well as progression to ACLF. Treatment of precipitating events and intensive organ support is the only established therapeutic strategies. Liver transplantationrepresents the only curative therapy but contraindications and organ scarcity limit its availability to only a minority of patients with end-stage liver disease. Therefore, the discovery and development of novel interventions modifying the disease course and improving patients' outcome are of utmost importance. AREAS COVERED This review highlights and discusses therapeutic novelties in the field of end-stage liver disease. EXPERT OPINION Despite decades of research, there are still no established therapies to improve the devastating prognosis of patients with end-stage liver disease. The clinical heterogeneity and complex pathogenesis will put high demands on drug discovery. Combinatorial therapies tailored to the patients' individual pattern of pathomechanisms may be the most efficient way to modify disease course.
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Affiliation(s)
- Sven Lamatsch
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Richard Sittner
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany.,Berlin Institute of Health at Charité (BIH) - BIH Biomedical Innovation Academy, Berlin, Germany.,Institute for Liver and Digestive Health, University College London, London, UK
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20
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Lücke J, Sabihi M, Zhang T, Bauditz LF, Shiri AM, Giannou AD, Huber S. The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies. Semin Immunopathol 2021; 43:591-607. [PMID: 33851257 PMCID: PMC8443499 DOI: 10.1007/s00281-021-00854-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/23/2021] [Indexed: 12/17/2022]
Abstract
The human liver fulfills several vital tasks daily and possesses an impressive ability to self-regenerate. However, the capacity of this self-healing process can be exhausted by a variety of different liver diseases, such as alcoholic liver damage, viral hepatitis, or hepatocellular carcinoma. Over time, all these diseases generally lead to progressive liver failure that can become fatal if left untreated. Thus, a great effort has been directed towards the development of innovative therapies. The most recently discovered therapies often involve modifying the patient's immune system to enhance a beneficial immune response. Current data suggest that, among others, the cytokine IL-22 might be a promising therapeutical candidate. IL-22 and its endogenous antagonist, IL-22BP, have been under thorough scientific investigation for nearly 20 years. While IL-22 is mainly produced by TH22 cells, ILC3s, NKT cells, or γδ T cells, sources of IL-22BP include dendritic cells, eosinophils, and CD4+ cells. In many settings, IL-22 was shown to promote regenerative potential and, thus, could protect tissues from pathogens and damage. However, the effects of IL-22 during carcinogenesis are more ambiguous and depend on the tumor entity and microenvironment. In line with its capabilities of neutralizing IL-22 in vivo, IL-22BP possesses often, but not always, an inverse expression pattern compared to its ligand. In this comprehensive review, we will summarize past and current findings regarding the roles of IL-22 and IL-22BP in liver diseases with a particular focus on the leading causes of advanced liver failure, namely, liver infections, liver damage, and liver malignancies.
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Affiliation(s)
- Jöran Lücke
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Morsal Sabihi
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Tao Zhang
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Lennart Fynn Bauditz
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Ahmad Mustafa Shiri
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Anastasios D Giannou
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
| | - Samuel Huber
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
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21
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Ho CM, Chen CL, Chang CH, Lee MR, Wang JY, Hu RH, Lee PH. Circulatory Inflammatory Mediators in the Prediction of Anti-Tuberculous Drug-Induced Liver Injury Using RUCAM for Causality Assessment. Biomedicines 2021; 9:891. [PMID: 34440095 PMCID: PMC8389605 DOI: 10.3390/biomedicines9080891] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Anti-tuberculous (TB) medications are common causes of drug-induced liver injury (DILI). Limited data are available on systemic inflammatory mediators as biomarkers for predicting DILI before treatment. We aimed to select predictive markers among potential candidates and to formulate a predictive model of DILI for TB patients. METHODS Adult active TB patients from a prospective cohort were enrolled, and all participants received standard anti-tuberculous treatment. Development of DILI, defined as ≥5× ULN for alanine transaminase or ≥2.6× ULN of total bilirubin with causality assessment (RUCAM, Roussel Uclaf causality assessment method), was regularly monitored. Pre-treatment plasma was assayed for 15 candidates, and a set of risk prediction scores was established using Cox regression and receiver-operating characteristic analyses. RESULTS A total of 19 (7.9%) in 240 patients developed DILI (including six carriers of hepatitis B virus) following anti-TB treatment. Interleukin (IL)-22 binding protein (BP), interferon gamma-induced protein 1 (IP-10), soluble CD163 (sCD163), IL-6, and CD206 were significant univariable factors associated with DILI development, and the former three were backward selected as multivariable factors, with adjusted hazards of 0.20 (0.07-0.58), 3.71 (1.35-10.21), and 3.28 (1.07-10.06), respectively. A score set composed of IL-22BP, IP-10, and sCD163 had an improved area under the curve of 0.744 (p < 0.001). CONCLUSIONS Pre-treatment IL-22BP was a protective biomarker against DILI development under anti-TB treatment, and a score set by additional risk factors of IP-10 and sCD163 employed an adequate DILI prediction.
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Affiliation(s)
- Cheng-Maw Ho
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei 10617, Taiwan; (C.-M.H.); (R.-H.H.); (P.-H.L.)
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei 10617, Taiwan;
| | - Chia-Hao Chang
- Department of Internal Medicine, National Taiwan University Hospital, Hsinchu Branch, Hsinchu City 300, Taiwan; (C.-H.C.); (M.-R.L.)
| | - Meng-Rui Lee
- Department of Internal Medicine, National Taiwan University Hospital, Hsinchu Branch, Hsinchu City 300, Taiwan; (C.-H.C.); (M.-R.L.)
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 10617, Taiwan
| | - Jann-Yuan Wang
- Department of Internal Medicine, National Taiwan University Hospital, Hsinchu Branch, Hsinchu City 300, Taiwan; (C.-H.C.); (M.-R.L.)
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 10617, Taiwan
| | - Rey-Heng Hu
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei 10617, Taiwan; (C.-M.H.); (R.-H.H.); (P.-H.L.)
| | - Po-Huang Lee
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei 10617, Taiwan; (C.-M.H.); (R.-H.H.); (P.-H.L.)
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22
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Zhou H, Xu J, Huang S, He Y, He X, Guo L, Yin S, Lu S. Blocking the Hepatic Branch of the Vagus Aggravates Hepatic Ischemia-Reperfusion Injury via Inhibiting the Expression of IL-22 in the Liver. J Immunol Res 2021; 2021:6666428. [PMID: 34514001 PMCID: PMC8429033 DOI: 10.1155/2021/6666428] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/20/2021] [Accepted: 04/27/2021] [Indexed: 12/02/2022] Open
Abstract
Liver ischemia-reperfusion injury (IRI) is an inevitable process during liver transplantation, hemorrhagic shock, resection, and other liver surgeries. It is an important cause of postoperative liver dysfunction and increased medical costs. The protective effects of the vagus nerve on hepatic IRI have been reported, but the underlying mechanism has not been fully understood. We established a hepatic vagotomy (Hv) mouse model to study the effect of the vagus on liver IRI and to explore the underlying mechanism. Liver IRI was more serious in mice with Hv, which showed higher serum ALT and AST activities and histopathological changes. Further experiments confirmed that Hv significantly downregulated the expression of IL-22 protein and mRNA in the liver, blocking the activation of the STAT3 pathway. The STAT3 pathway in the livers of Hv mice was significantly activated, and liver injury was clearly alleviated after treatment with exogenous IL-22 recombinant protein. In conclusion, Hv can aggravate hepatic IRI, and its mechanism may be related to inhibition of IL-22 expression and downregulation of the STAT3 pathway in the liver.
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Affiliation(s)
- Heng Zhou
- Department of Pharmacy, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, China
| | - Juling Xu
- Medical School of Huzhou University, Huzhou 313000, China
| | - Sanxiong Huang
- Department of Hepatobiliary Surgery, The First People's Hospital of Huzhou, Huzhou 313000, China
| | - Ying He
- Zhejiang Provincial Key Laboratory of Media Biology and Pathogenic Control, Central Laboratory, First Affiliated Hospital of Huzhou University, Huzhou 313000, China
| | - Xiaowei He
- Department of Pharmacy, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, China
| | - Lu Guo
- Department of Pharmacy, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, China
| | - Shi Yin
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Sheng Lu
- Department of Pharmacy, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou 313000, China
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23
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Rueschenbaum S, Ciesek S, Queck A, Widera M, Schwarzkopf K, Brüne B, Welsch C, Wedemeyer H, Zeuzem S, Weigert A, Lange CM. Dysregulated Adaptive Immunity Is an Early Event in Liver Cirrhosis Preceding Acute-on-Chronic Liver Failure. Front Immunol 2021; 11:534731. [PMID: 33574809 PMCID: PMC7870861 DOI: 10.3389/fimmu.2020.534731] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction Acute-on-chronic liver failure (ACLF) is characterized by high levels of systemic inflammation and parallel suppression of innate immunity, whereas little is known about adaptive immune immunity in ACLF. We therefore aimed to characterize the development of the adaptive immune system during the progression of liver cirrhosis to ACLF. Patients with compensated/stable decompensated liver cirrhosis, acute decompensation of liver cirrhosis, or ACLF were recruited from a prospective cohort study. Comprehensive immunophenotyping was performed using high dimensional flow cytometry. Replication of Torque teno (TT) virus was quantified as a marker of immunosuppression. High frequencies of detectable TT virus were observed already in patients with compensated/stable decompensated liver cirrhosis compared to healthy controls (>50% vs. 19%), suggesting relatively early occurrence of immunosuppression in cirrhosis. In line, profoundly reduced numbers of distinct innate and adaptive immune cell populations were observed before ACLF development. These changes were accompanied by parallel upregulation of co-stimulatory (e.g. CD40L, OX40, CD69, GITR, TIM-1) and inhibitory immune checkpoints (e.g. PDPN, PROCR, 2B4, TIGIT) on CD4+ and CD8+ T cells, which again preceded the development of ACLF. On a functional basis, the capacity of CD4+ and CD8+ T cells to produce pro-inflammatory cytokines upon stimulation was strongly diminished in patients with acute decompensation of liver cirrhosis and ACLF. Conclusion Impaired innate and—in particular—adaptive cellular immunity occurs relatively early in the pathogenesis of liver cirrhosis and precedes ACLF. This may contribute to the development of ACLF by increasing the risk of infections in patients with liver cirrhosis.
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Affiliation(s)
- Sabrina Rueschenbaum
- Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany.,Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Sandra Ciesek
- Institute of Virology, University Hospital Essen, Essen, Germany
| | - Alexander Queck
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Marek Widera
- Institute of Virology, University Hospital Essen, Essen, Germany
| | - Katharina Schwarzkopf
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Bernhard Brüne
- Faculty of Medicine, Institute of Biochemistry 1, Goethe-University Frankfurt, Frankfurt, Germany
| | - Christoph Welsch
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Andreas Weigert
- Faculty of Medicine, Institute of Biochemistry 1, Goethe-University Frankfurt, Frankfurt, Germany
| | - Christian M Lange
- Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany.,Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
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24
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Rueschenbaum S, Cai C, Schmidt M, Schwarzkopf K, Dittmer U, Zeuzem S, Welsch C, Lange CM. Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity. Front Immunol 2021; 11:581352. [PMID: 33584648 PMCID: PMC7874116 DOI: 10.3389/fimmu.2020.581352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/30/2020] [Indexed: 12/18/2022] Open
Abstract
Interleukin-7 (IL-7) is an important cytokine with pivotal pro-survival functions in the adaptive immune system. However, the role of IL-7 in innate immunity is not fully understood. In the present study, the impact of hepatic IL-7 on innate immune cells was assessed by functional experiments as well as in patients with different stages of liver cirrhosis or acute-on-chronic liver failure (ACLF). Human hepatocytes and liver sinusoidal endothelial cells secreted IL-7 in response to stimulation with interferons (IFNs) of type I and II, yet not type III. De novo translation of interferon-response factor-1 (IRF-1) restricted IL-7 production to stimulation with type I and II IFNs. LPS-primed human macrophages were identified as innate immune target cells responding to IL-7 signaling by inactivation of Glycogen synthase kinase-3 (GSK3). IL-7-mediated GSK3 inactivation augmented LPS-induced secretion of pro-inflammatory cytokines and blunted LPS tolerance of macrophages. The IFN-IRF-1-IL-7 axis was present in liver cirrhosis patients. However, liver cirrhosis patients with or without ACLF had significantly lower concentrations of IL-7 in serum compared to healthy controls, which might contribute to LPS-tolerance in these patients. In conclusion, we propose the presence of an inflammatory cascade where IFNs of type I/II induce hepatocellular IL-7 in an IRF-1-restriced way. Beyond its role in adaptive immune responses, IL-7 appears to augment the response of macrophages to LPS and to ameliorate LPS tolerance, which may improve innate immune responses against invading pathogens.
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Affiliation(s)
- Sabrina Rueschenbaum
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Chengcong Cai
- Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Matthias Schmidt
- Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | | | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Stefan Zeuzem
- Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Christoph Welsch
- Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Christian M Lange
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
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25
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He Y, Hwang S, Ahmed YA, Feng D, Li N, Ribeiro M, Lafdil F, Kisseleva T, Szabo G, Gao B. Immunopathobiology and therapeutic targets related to cytokines in liver diseases. Cell Mol Immunol 2021; 18:18-37. [PMID: 33203939 PMCID: PMC7853124 DOI: 10.1038/s41423-020-00580-w] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 10/15/2020] [Indexed: 02/07/2023] Open
Abstract
Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma. The progression of liver disease is controlled by a variety of factors, including liver injury, inflammatory cells, inflammatory mediators, cytokines, and the gut microbiome. In the current review, we discuss recent data on a large number of cytokines that play important roles in regulating liver injury, inflammation, fibrosis, and regeneration, with a focus on interferons and T helper (Th) 1, Th2, Th9, Th17, interleukin (IL)-1 family, IL-6 family, and IL-20 family cytokines. Hepatocytes can also produce certain cytokines (such as IL-7, IL-11, and IL-33), and the functions of these cytokines in the liver are briefly summarized. Several cytokines have great therapeutic potential, and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases, which are also described.
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Affiliation(s)
- Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Yeni Ait Ahmed
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
- Université Paris-Est, UMR-S955, UPEC, F-94000, Créteil, France
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Na Li
- Department of Medicine and Department of Surgery, School of Medicine, University of California, San Diego, CA, 92093, USA
| | - Marcelle Ribeiro
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Fouad Lafdil
- Université Paris-Est, UMR-S955, UPEC, F-94000, Créteil, France
- INSERM, U955, F-94000, Créteil, France
- Institut Universitaire de France (IUF), Paris, F-75231, Cedex 05, France
| | - Tatiana Kisseleva
- Department of Medicine and Department of Surgery, School of Medicine, University of California, San Diego, CA, 92093, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA.
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26
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Sakemi R, Mitsuyama K, Morita M, Yoshioka S, Kuwaki K, Tokuyasu H, Fukunaga S, Mori A, Araki T, Yoshimura T, Yamasaki H, Tsuruta K, Morita T, Yamasaki S, Mizoguchi A, Sou S, Torimura T. Altered serum profile of the interleukin-22 system in inflammatory bowel disease. Cytokine 2020; 136:155264. [PMID: 32920320 DOI: 10.1016/j.cyto.2020.155264] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 08/17/2020] [Accepted: 08/20/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIM Interleukin-22 (IL-22), plays a vital role in the mucosal repair of inflammatory bowel disease (IBD). Serum levels of IL-22 and IL-22 binding protein (IL-22BP), a soluble inhibitory IL-22 receptor, were measured in patients with IBD to investigate the profile of IL-22 in the systemic circulation. METHODS Blood samples from 92 healthy subjects, 98 patients with ulcerative colitis (UC), and 105 patients with Crohn's disease (CD) were analyzed for serum levels of IL-22, IL-22BP, human β-defensin 2 (hBD-2), and serum inflammatory parameters. Disease activity was assessed by the partial Mayo score and Harvey-Bradshaw index for UC and CD, respectively. RESULTS Serum IL-22 level was lower in UC (P < 0.001) and CD (P < 0.001) vs control and its decrease was more pronounced in CD than in UC (P = 0.019). Serum IL-22BP level was lower in UC (P < 0.001) and CD (P < 0.001) vs control and correlated with inflammatory parameters (albumin and C-reactive protein (CRP) in UC; hemoglobin, albumin, and CRP in CD). Serum IL-22/IL-22BP ratios were higher in UC (P = 0.009) vs control and correlated with inflammatory parameters (albumin and CRP). Serum hBD-2 level was higher only in CD (P = 0.015) but did not correlate with serum IL-22 levels, IL-22BP levels, IL-22/IL-22BP ratios, or inflammatory parameters. CONCLUSIONS Dysregulation of the IL-22 system in the blood may play a role in the pathogenesis of IBD. Further studies are needed to understand the pathogenic and clinical significance of the blood IL-22 system in IBD.
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Affiliation(s)
- Ryosuke Sakemi
- Department of Gastroenterology, Tobata Kyoritsu Hospital, 2-5-1 Sawami, Tobata-ku, Kitakyushu 804-0093, Japan
| | - Keiichi Mitsuyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan; Inflammatory Bowel Disease Center, Kurume University Hospital, 67 Asahi-machi, Kurume 830-0011, Japan.
| | - Masaru Morita
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Shinichiro Yoshioka
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Kotaro Kuwaki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Hidenori Tokuyasu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Shuhei Fukunaga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Atsushi Mori
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Toshihiro Araki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Tetsuhiro Yoshimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Hiroshi Yamasaki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Kozo Tsuruta
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Taku Morita
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Sayo Yamasaki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Atsushi Mizoguchi
- Department of Immunology, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Suketo Sou
- Department of Gastroenterology, Tobata Kyoritsu Hospital, 2-5-1 Sawami, Tobata-ku, Kitakyushu 804-0093, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
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27
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Khanam A, Kottilil S. Abnormal Innate Immunity in Acute-on-Chronic Liver Failure: Immunotargets for Therapeutics. Front Immunol 2020; 11:2013. [PMID: 33117329 PMCID: PMC7578249 DOI: 10.3389/fimmu.2020.02013] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a severe life-threatening condition with high risk of multiorgan failure, sepsis, and mortality. ACLF activates a multifaceted interplay of both innate and adaptive immune response in the host which governs the overall outcome. Innate immune cells recognize the conserved elements of microbial and viral origin, both to extort instant defense by transforming into diverse modules of effector responses and to generate long-lasting immunity but can also trigger a massive intrahepatic immune inflammatory response. Acute insult results in the activation of innate immune cells which provokes cytokine and chemokine cascade and subsequently initiates aggressive systemic inflammatory response syndrome, hepatic damage, and high mortality in ACLF. Dysregulated innate immune response not only plays a critical role in disease progression but also potentially correlates with clinical disease severity indices including Child-Turcotte-Pugh, a model for end-stage liver disease, and sequential organ failure assessment score. A better understanding of the pathophysiological basis of the disease and precise immune mechanisms associated with liver injury offers a novel approach for the development of new and efficient therapies to treat this severely ill entity. Immunotherapies could be helpful in targeting immune-mediated organ damage which may constrain progression toward liver failure and eventually reduce the requirement for liver transplantation. Here, in this review we discuss the defects of different innate immune cells in ACLF which updates the current knowledge of innate immune response and provide potential targets for new therapeutic interventions.
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Affiliation(s)
- Arshi Khanam
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
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Mücke VT, Maria Schwarzkopf K, Thomas D, Mücke MM, Rüschenbaum S, Trebicka J, Pfeilschifter J, Zeuzem S, Lange CM, Grammatikos G. Serum Sphingosine-1-Phosphate Is Decreased in Patients With Acute-on-Chronic Liver Failure and Predicts Early Mortality. Hepatol Commun 2020; 4:1477-1486. [PMID: 33024917 PMCID: PMC7527696 DOI: 10.1002/hep4.1561] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/17/2020] [Accepted: 06/10/2020] [Indexed: 12/30/2022] Open
Abstract
Sphingosine‐1‐phosphate (S1P) regulates pathophysiological processes, including liver regeneration, vascular tone control, and immune response. In patients with liver cirrhosis, acute deterioration of liver function is associated with high mortality rates. The present study investigated whether serum S1P concentrations are associated with disease severity in patients with chronic liver disease from compensated cirrhosis (CC), acute decompensation (AD), or acute‐on‐chronic liver failure (ACLF). From August 2013 to October 2017, patients who were admitted to the University Hospital Frankfurt with CC, AD, or ACLF were enrolled in our cirrhosis cohort study. Tandem mass spectrometry was performed on serum samples of 127 patients to assess S1P concentration. Our study comprised 19 patients with CC, 55 with AD, and 51 with ACLF, aged 29 to 76 years. We observed a significant decrease of S1P according to advanced liver injury from CC and AD up to ACLF (P < 0.001). S1P levels further decreased with progression to ACLF grade 3 (P < 0.05), and S1P highly inversely correlated with the Model for End‐Stage Liver Disease score (r = −0.508; P < 0.001). In multivariate analysis, S1P remained an independent predictor of 7‐day mortality with high diagnostic accuracy (area under the curve, 0.874; P < 0.001). Conclusion: In patients with chronic liver disease, serum S1P levels dramatically decreased with advanced stages of liver disease and were predictive of early mortality. Because S1P is a potent regulator of endothelial integrity and immune response, low S1P levels may significantly influence progressive multiorgan failure. Our data justify further elucidation of the diagnostic and therapeutic role of S1P in ACLF.
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Affiliation(s)
- Victoria T Mücke
- Departement of Internal Medicine 1 University Hospital Frankfurt Goethe University Frankfurt am Main Germany
| | - Katharina Maria Schwarzkopf
- Departement of Internal Medicine 1 University Hospital Frankfurt Goethe University Frankfurt am Main Germany
| | - Dominique Thomas
- Pharmazentrum Frankfurt Institute of Clinical Pharmacology Goethe University Frankfurt am Main Germany
| | - Marcus M Mücke
- Departement of Internal Medicine 1 University Hospital Frankfurt Goethe University Frankfurt am Main Germany
| | - Sabrina Rüschenbaum
- Department of Gastroenterology and Hepatology University Hospital Essen University of Duisburg-Essen Essen Germany
| | - Jonel Trebicka
- Departement of Internal Medicine 1 University Hospital Frankfurt Goethe University Frankfurt am Main Germany
| | - Josef Pfeilschifter
- Pharmazentrum Frankfurt Institute of General Pharmacology and Toxicology Goethe University Frankfurt am Main Germany
| | - Stefan Zeuzem
- Departement of Internal Medicine 1 University Hospital Frankfurt Goethe University Frankfurt am Main Germany
| | - Christian M Lange
- Department of Gastroenterology and Hepatology University Hospital Essen University of Duisburg-Essen Essen Germany
| | - Georgios Grammatikos
- Departement of Internal Medicine 1 University Hospital Frankfurt Goethe University Frankfurt am Main Germany.,St. Luke's Hospital Thessaloniki Panorama Greece
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Xiang X, Hwang S, Gao B. Reply to: "Interleukin-22 in acute-on-chronic liver failure: A matter of ineffective levels, receptor dysregulation or defective signalling?": The search for an optimal mouse model. J Hepatol 2020; 73:982-984. [PMID: 32690377 DOI: 10.1016/j.jhep.2020.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/03/2020] [Accepted: 06/03/2020] [Indexed: 12/04/2022]
Affiliation(s)
- Xiaogang Xiang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
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Schwarzkopf KM, Eberle L, Uschner FE, Klein S, Schierwagen R, Mücke MM, Schaefer L, Clària J, Zeuzem S, Hintermann E, Christen U, Lange CM, Trebicka J, Welsch C. Interleukin-22 in acute-on-chronic liver failure: A matter of ineffective levels, receptor dysregulation or defective signalling? J Hepatol 2020; 73:980-982. [PMID: 32698966 DOI: 10.1016/j.jhep.2020.05.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/12/2020] [Accepted: 05/12/2020] [Indexed: 01/16/2023]
Affiliation(s)
- Katharina Maria Schwarzkopf
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Larissa Eberle
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Frank Erhard Uschner
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Sabine Klein
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Robert Schierwagen
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Marcus Maximilian Mücke
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Liliana Schaefer
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Joan Clària
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Hospital Clínic-IDIBAPS, Barcelona, Spain
| | - Stefan Zeuzem
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Christian Markus Lange
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Jonel Trebicka
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain.
| | - Christoph Welsch
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
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Xiang X, Hwang S, Feng D, Shah VH, Gao B. Interleukin-22 in alcoholic hepatitis and beyond. Hepatol Int 2020; 14:667-676. [PMID: 32892258 PMCID: PMC7572732 DOI: 10.1007/s12072-020-10082-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022]
Abstract
Alcoholic hepatitis (AH) is a clinical syndrome characterized by jaundice and progressive inflammatory liver injury in patients with a history of prolonged periods of excess alcohol consumption and recent heavy alcohol abuse. Severe AH is a life-threatening form of alcohol-associated liver disease with a high short-term mortality rate around 30-50% at one month from the initial presentation. A large number of pro-inflammatory mediators, metabolic pathways, transcriptional factors and epigenetic factors have been suggested to be associated with the development and progression of AH. Several factors may contribute to liver failure and mortality in patients with severe AH including hepatocyte death, inflammation, and impaired liver regeneration. Although the pathogeneses of AH have been extensively investigated and many therapeutic targets have been identified over the last five decades, no new drugs for AH have been successfully developed. In this review, we discuss interleukin-22 (IL-22) biology and its roles of anti-apoptosis, anti-fibrosis, anti-oxidation, anti-bacterial infection and regenerative stimulation in protecting against liver injury in many preclinical models including several recently developed models such as chronic-plus-binge ethanol feeding, acute-on-chronic liver failure, C-X-C motif chemokine ligand 1 plus high-fat diet-induced nonalcoholic steatohepatitis. Finally, clinical trials of IL-22 for the treatment of AH are also discussed, which showed some promising benefits for AH patients.
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Affiliation(s)
- Xiaogang Xiang
- Department of Infectious Diseases, Translational Laboratory of Liver Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Laboratory of Liver Diseases, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55902, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA.
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Arab JP, Sehrawat TS, Simonetto DA, Verma VK, Feng D, Tang T, Dreyer K, Yan X, Daley WL, Sanyal A, Chalasani N, Radaeva S, Yang L, Vargas H, Ibacache M, Gao B, Gores GJ, Malhi H, Kamath PS, Shah VH. An Open-Label, Dose-Escalation Study to Assess the Safety and Efficacy of IL-22 Agonist F-652 in Patients With Alcohol-associated Hepatitis. Hepatology 2020; 72:441-453. [PMID: 31774566 PMCID: PMC7250715 DOI: 10.1002/hep.31046] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 11/07/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of human interleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH. APPROACH AND RESULTS A phase-2 dose-escalating study was carried out. F-652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day-7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down-regulated, and regeneration markers were up-regulated at days 28 and 42. CONCLUSIONS F-652 is safe in doses up to 45 μg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo-controlled trials to test the efficacy of F-652 in AH.
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Affiliation(s)
- Juan P. Arab
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, CHILE
| | - Tejasav S. Sehrawat
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | | | - Vikas K. Verma
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Tom Tang
- Generon Corporation Ltd. Shanghai, China
| | | | | | | | - Arun Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Naga Chalasani
- Indiana University School of Medicine, Indianapolis, IN, USA
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Liu Yang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Hugo Vargas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - Mauricio Ibacache
- División Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, CHILE
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Patrick S. Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Xiang X, Feng D, Hwang S, Ren T, Wang X, Trojnar E, Matyas C, Mo R, Shang D, He Y, Seo W, Shah VH, Pacher P, Xie Q, Gao B. Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming impaired regeneration pathways in mice. J Hepatol 2020; 72:736-745. [PMID: 31786256 PMCID: PMC7085428 DOI: 10.1016/j.jhep.2019.11.013] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 11/13/2019] [Accepted: 11/13/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Acute-on-chronic liver failure (ACLF) is a clinical syndrome defined by liver failure on pre-existing chronic liver disease. It is often associated with bacterial infection and high short-term mortality. Experimental models that fully reproduce ACLF are lacking, so too are effective pharmacological therapies for this condition. METHODS To mimic ACLF conditions, we developed a severe liver injury model by combining chronic injury (chronic carbon tetrachloride [CCl4] injection), acute hepatic insult (injection of a double dose of CCl4), and bacterial infection (intraperitoneal injection of bacteria). Serum and liver samples from patients with ACLF or acute drug-induced liver injury (DILI) were used. Liver injury and regeneration were assessed to ascertain the potential benefits of interleukin-22 (IL-22Fc) administration. RESULTS This severe liver injury model recapitulated some of the key features of clinical ACLF, including acute-on-chronic liver injury, bacterial infection, multi-organ injury, and high mortality. Liver regeneration in this model was severely impaired because of a shift from the activation of the pro-regenerative IL-6/STAT3 pathway to the anti-regenerative IFN-γ/STAT1 pathway. The impaired IL-6/STAT3 activation was due to the inability of Kupffer cells to produce IL-6; whereas the enhanced STAT1 activation was due to a strong innate immune response and subsequent production of IFN-γ. Compared to patients with DILI, patients with ACLF had higher levels of IFN-γ but lower liver regeneration. IL-22Fc treatment improved survival in ACLF mice by reversing the STAT1/STAT3 pathway imbalance and enhancing expression of many antibacterial genes in a manner involving the anti-apoptotic protein BCL2. CONCLUSIONS Acute-on-chronic liver injury or bacterial infection is associated with impaired liver regeneration due to a shift from a pro-regenerative to an anti-regenerative pathway. IL-22Fc therapy reverses this shift and attenuates bacterial infection, thus IL-22Fc may have therapeutic potential for ACLF treatment. LAY SUMMARY A mouse model combining chronic liver injury, acute hepatic insult, and bacterial infection recapitulates some of the key features of acute-on-chronic liver failure (ACLF) in patients. Both fibrosis and bacterial infection contribute to the impaired regenerative capacity of the liver in patients with ACLF. Herein, we show that IL-22Fc therapy improves ACLF by reprogramming impaired regenerative pathways and attenuating bacterial infection. Thus, it may have therapeutic potential for patients with ACLF.
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Affiliation(s)
- Xiaogang Xiang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA; Department of Infectious Diseases, Translational Laboratory of Liver Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tianyi Ren
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Xiaolin Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Eszter Trojnar
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA
| | - Csaba Matyas
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA
| | - Ruidong Mo
- Department of Infectious Diseases, Translational Laboratory of Liver Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Dabao Shang
- Department of Infectious Diseases, Translational Laboratory of Liver Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Wonhyo Seo
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA
| | - Qing Xie
- Department of Infectious Diseases, Translational Laboratory of Liver Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA.
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Engelmann C, Mehta G, Tacke F. Regeneration in acute-on-chronic liver failure - the phantom lost its camouflage. J Hepatol 2020; 72:610-612. [PMID: 31953140 DOI: 10.1016/j.jhep.2020.01.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 01/01/2020] [Accepted: 01/02/2020] [Indexed: 02/07/2023]
Affiliation(s)
- Cornelius Engelmann
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom; Section Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany; Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Charité Campus Mitte, Charité - Universitaetsmedizin Berlin, Berlin, Germany
| | - Gautam Mehta
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom; Institute of Hepatology, Foundation for Liver Research, London, United Kingdom; Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Charité Campus Mitte, Charité - Universitaetsmedizin Berlin, Berlin, Germany.
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Che Y, Su Z, Xia L. Effects of IL-22 on cardiovascular diseases. Int Immunopharmacol 2020; 81:106277. [PMID: 32062077 DOI: 10.1016/j.intimp.2020.106277] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 01/29/2020] [Accepted: 02/01/2020] [Indexed: 12/11/2022]
Abstract
Interleukin-22 (IL-22), which belongs to the IL-10 family, is an alpha helix cytokine specifically produced by many lymphocytes, such as Th1, Th17, Th22, ILCs, CD4+ and CD8+ T cells. In recent years, more and more studies have demonstrated that IL-22 has an interesting relationship with various cardiovascular diseases, including myocarditis, myocardial infarction, atherosclerosis, and other cardiovascular diseases, and IL-22 signal may play a dual role in cardiovascular diseases. Here, we summarize the recent progress on the source, function, regulation of IL-22 and the effects of IL-22 signal in cardiovascular diseases. The study of IL-22 will suggest more specific strategies to maneuver these functions for the effective treatment of cardiovascular diseases and future clinical treatment.
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Affiliation(s)
- Yang Che
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China; International Genome Center, Jiangsu University, Zhenjiang 212013, China
| | - Zhaoliang Su
- International Genome Center, Jiangsu University, Zhenjiang 212013, China; Department of Immunology, Jiangsu University, Zhenjiang 212013, China
| | - Lin Xia
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China; International Genome Center, Jiangsu University, Zhenjiang 212013, China.
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Mühl H, Bachmann M. IL-18/IL-18BP and IL-22/IL-22BP: Two interrelated couples with therapeutic potential. Cell Signal 2019; 63:109388. [PMID: 31401146 DOI: 10.1016/j.cellsig.2019.109388] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/07/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023]
Abstract
Interleukin (IL)-18 and IL-22 are key components of cytokine networks that play a decisive role in (pathological) inflammation, host defense, and tissue regeneration. Tight regulation of cytokine-driven signaling, inflammation, and immunoactivation is supposed to enable nullification of a given deleterious trigger without mediating overwhelming collateral tissue damage or even activating a cancerous face of regeneration. In fact, feedback regulation by specific cytokine opponents is regarded as a major means by which the immune system is kept in balance. Herein, we shine a light on the interplay between IL-18 and IL-22 and their opponents IL-18 binding protein (IL-18BP) and IL-22BP in order to provide integrated information on their biology, pathophysiological significance, and prospect as targets and/or instruments of therapeutic intervention.
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Affiliation(s)
- Heiko Mühl
- pharmazentrum frankfurt/ZAFES, University Hospital Goethe University Frankfurt am Main, Theodor-Stern- Kai 7, 60590 Frankfurt am Main, Germany.
| | - Malte Bachmann
- pharmazentrum frankfurt/ZAFES, University Hospital Goethe University Frankfurt am Main, Theodor-Stern- Kai 7, 60590 Frankfurt am Main, Germany
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