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1
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Aliaga-Gaspar P, Brichette-Mieg I, Fernández-Arjona M, Rodríguez-Bada JL, López-Moreno Y, Serrano-Castro P, Fernández-Fernández O, Ciano-Petersen NL, Oliver-Martos B. Recombinant soluble type I interferon receptor exerts antiviral activity by inducing proteins related to autophagy. Biomed Pharmacother 2024; 181:117678. [PMID: 39577364 DOI: 10.1016/j.biopha.2024.117678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/25/2024] [Accepted: 11/07/2024] [Indexed: 11/24/2024] Open
Abstract
The soluble type I IFN receptor (sIFNAR2) is produced by alternative splicing and is present in body fluids. Although it can modulate IFN-ß activity, its biological role remains unknown. METHODS An in-silico study was conducted to compare the structure of recombinant human soluble IFNAR2 (r-sIFNAR2) with its native form. The antiviral activity of r-sIFNAR2, produced in BL21-bacteria and CHO cells, was tested using a cytopathic effect assay including appropriate controls. Viability and toxicity were assessed by MTT assays. Proteomic analysis using mass spectrometry was conducted in the A549/EMCV bioassay to elucidate the mechanism of action, and then it was validated by Western blot. RESULTS The BL21-sIFNAR2 had a sequence identity of 83.6 % with the native form, showing variations only in terminal regions. BL21-sIFNAR2 and CHO-sIFNAR2 showed significantly higher percentage of cell viability compared to the viral control, similar to IFN-ß. Cell viability with BL21-sIFNAR2 was comparable to the cell control across all tested concentrations. Proteomic analysis revealed an up regulation of pathways related with autophagy (macroautophagy, autophagy, pexophagy, and mitophagy) with an SQSTM1 overexpression that was then confirmed by Western Blot, especially after virus infection. However, pathways related to interferon signaling, and antiviral mechanisms mediated by IFN-stimulated genes were down-regulated. CONCLUSION r-sIFNAR2 exhibits significant antiviral activity regardless of the expression system used for its production and good safety profile, suggesting its use as a potential antiviral drug. Proteins related to autophagy are involved in the protection from the virus. This study highlights the biological relevance of soluble cytokine receptors as effectors so far overlooked.
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Affiliation(s)
- Pablo Aliaga-Gaspar
- Neuroimmunology and Neuroinflammation group. Biomedical Research Institute of Málaga-IBIMA Plataforma Bionand Hospital Regional Universitario de Málaga, Málaga, Spain; Facultad de Medicina, Universidad de Málaga, Málaga, Spain
| | - Isabel Brichette-Mieg
- Neuroimmunology and Neuroinflammation group. Biomedical Research Institute of Málaga-IBIMA Plataforma Bionand Hospital Regional Universitario de Málaga, Málaga, Spain
| | - MdM Fernández-Arjona
- Neuroimmunology and Neuroinflammation group. Biomedical Research Institute of Málaga-IBIMA Plataforma Bionand Hospital Regional Universitario de Málaga, Málaga, Spain
| | - José Luis Rodríguez-Bada
- Neuroimmunology and Neuroinflammation group. Biomedical Research Institute of Málaga-IBIMA Plataforma Bionand Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Yolanda López-Moreno
- Neuroimmunology and Neuroinflammation group. Biomedical Research Institute of Málaga-IBIMA Plataforma Bionand Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Pedro Serrano-Castro
- Neuroimmunology and Neuroinflammation group. Biomedical Research Institute of Málaga-IBIMA Plataforma Bionand Hospital Regional Universitario de Málaga, Málaga, Spain; Red Andaluza de Investigación Clínica y Traslacional en Neurología (Neuro-RECA), Málaga, Spain; Department of Medicine and Dermatology, Faculty of Medicine, University of Málaga, Málaga, Spain
| | | | - Nicolás Lundahl Ciano-Petersen
- Neuroimmunology and Neuroinflammation group. Biomedical Research Institute of Málaga-IBIMA Plataforma Bionand Hospital Regional Universitario de Málaga, Málaga, Spain; Red Andaluza de Investigación Clínica y Traslacional en Neurología (Neuro-RECA), Málaga, Spain.
| | - Begoña Oliver-Martos
- Neuroimmunology and Neuroinflammation group. Biomedical Research Institute of Málaga-IBIMA Plataforma Bionand Hospital Regional Universitario de Málaga, Málaga, Spain; Facultad de Medicina, Universidad de Málaga, Málaga, Spain; Department of Cell Biology, Genetics and Physiology, Physiology Area, Faculty of Science University of Malaga, Málaga, Spain.
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2
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Zhao Q, Zhang R, Qiao C, Miao Y, Yuan Y, Zheng H. Ubiquitination network in the type I IFN-induced antiviral signaling pathway. Eur J Immunol 2023; 53:e2350384. [PMID: 37194705 DOI: 10.1002/eji.202350384] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/14/2023] [Accepted: 05/16/2023] [Indexed: 05/18/2023]
Abstract
Type I IFN (IFN-I) is the body's first line of defense against pathogen infection. IFN-I can induce cellular antiviral responses and therefore plays a key role in driving antiviral innate and adaptive immunity. Canonical IFN-I signaling activates the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, which induces the expression of IFN-stimulated genes and eventually establishes a complex antiviral state in the cells. Ubiquitin is a ubiquitous cellular molecule for protein modifications, and the ubiquitination modifications of protein have been recognized as one of the key modifications that regulate protein levels and/or signaling activation. Despite great advances in understanding the ubiquitination regulation of many signaling pathways, the mechanisms by which protein ubiquitination regulates IFN-I-induced antiviral signaling have not been explored until very recently. This review details the current understanding of the regulatory network of ubiquitination that critically controls the IFN-I-induced antiviral signaling pathway from three main levels, including IFN-I receptors, IFN-I-induced cascade signals, and effector IFN-stimulated genes.
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Affiliation(s)
- Qian Zhao
- International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China
| | - Renxia Zhang
- International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China
| | - Caixia Qiao
- International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China
| | - Ying Miao
- International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China
| | - Yukang Yuan
- International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China
| | - Hui Zheng
- International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China
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3
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Novick D. A natural goldmine of binding proteins and soluble receptors simplified their translation to blockbuster drugs, all in one decade. Front Immunol 2023; 14:1151620. [PMID: 36875111 PMCID: PMC9980337 DOI: 10.3389/fimmu.2023.1151620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 02/03/2023] [Indexed: 02/18/2023] Open
Abstract
Human urinary proteins are a goldmine of natural proteins a feature that simplifies their translation to biologics. Combining this goldmine together with the ligand-affinity-chromatography (LAC) purification method, proved a winning formula in their isolation. LAC specificity, efficiency, simplicity and inherent indispensability in the search for predictable and unpredictable proteins, is superior to other separation techniques. Unlimited amounts of recombinant cytokines and monoclonal antibodies (mAb) accelerated the "triumph". My approach concluded 35 years of worldwide pursuit for Type I IFN receptor (IFNAR2) and advanced the understanding of the signal transduction of this Type of IFN. TNF, IFNγ and IL-6 as baits enabled the isolation of their corresponding soluble receptors and N-terminal amino acid sequence of the isolated proteins facilitated the cloning of their cell surface counterparts. IL-18, IL-32, and heparanase as the baits yielded the corresponding unpredictable proteins: the antidote IL-18 Binding Protein (IL-18BP), the enzyme Proteinase 3 (PR3) and the hormone Resistin. IFNβ proved beneficial in Multiple Sclerosis and is a blockbuster drug, Rebif®. TNF mAbs translated into Remicade® to treat Crohn's disease. Enbrel® based on TBPII is for Rheumatoid Arthritis. Both are blockbusters. Tadekinig alfa™, a recombinant IL-18BP, is in phase III clinical study for inflammatory and autoimmune diseases. Seven years of continuous compassionate use of Tadekinig alfa™ in children born with mutations (NLRC4, XIAP) proved life-saving and is an example of tailored made medicine. IL-18 is a checkpoint biomarker in cancer and IL-18BP is planned recently to target cytokine storms resulting from CAR-T treatment and in COVID 19.
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Affiliation(s)
- Daniela Novick
- Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
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4
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Bruera S, Chavula T, Madan R, Agarwal SK. Targeting type I interferons in systemic lupus erythematous. Front Pharmacol 2023; 13:1046687. [PMID: 36726783 PMCID: PMC9885195 DOI: 10.3389/fphar.2022.1046687] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 12/05/2022] [Indexed: 01/18/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with systemic clinical manifestations including, but not limited to, rash, inflammatory arthritis, serositis, glomerulonephritis, and cerebritis. Treatment options for SLE are expanding and the increase in our understanding of the immune pathogenesis is leading to the development of new therapeutics. Autoantibody formation and immune complex formation are important mediators in lupus pathogenesis, but an important role of the type I interferon (IFN) pathway has been identified in SLE patients and mouse models of lupus. These studies have led to the development of therapeutics targeting type I IFN and related pathways for the treatment of certain manifestations of SLE. In the current narrative review, we will discuss the role of type I IFN in SLE pathogenesis and the potential translation of these data into strategies using type I IFN as a biomarker and therapeutic target for patients with SLE.
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Affiliation(s)
- Sebastian Bruera
- Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Thandiwe Chavula
- Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Riya Madan
- Section of General Internal Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Sandeep K. Agarwal
- Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
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5
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Zhao J, Tang Z, Selvaraju M, Johnson KA, Douglas JT, Gao PF, Petrassi HM, Wang MZ, Wang J. Cellular Target Deconvolution of Small Molecules Using a Selection-Based Genetic Screening Platform. ACS CENTRAL SCIENCE 2022; 8:1424-1434. [PMID: 36313155 PMCID: PMC9615120 DOI: 10.1021/acscentsci.2c00609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Indexed: 05/04/2023]
Abstract
Small-molecule drug target identification is an essential and often rate-limiting step in phenotypic drug discovery and remains a major challenge. Here, we report a novel platform for target identification of activators of signaling pathways by leveraging the power of a clustered regularly interspaced short palindromic repeats (CRISPR) knockout library. This platform links the expression of a suicide gene to the small-molecule-activated signaling pathway to create a selection system. With this system, loss-of-function screening using a CRISPR single-guide (sg) RNA library positively enriches cells in which the target has been knocked out. The identities of the drug targets and other essential genes required for the activity of small molecules of interest are then uncovered by sequencing. We tested this platform on BDW568, a newly discovered type-I interferon signaling activator, and identified stimulator of interferon genes (STING) as its target and carboxylesterase 1 (CES1) to be a key metabolizing enzyme required to activate BDW568 for target engagement. The platform we present here can be a general method applicable for target identification for a wide range of small molecules that activate different signaling pathways.
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Affiliation(s)
- Junxing Zhao
- Department
of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States
| | - Zhichao Tang
- Department
of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States
| | - Manikandan Selvaraju
- Department
of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States
| | - Kristen A. Johnson
- Calibr,
Scripps Research Institute, La Jolla, California 92037, United States
| | - Justin T. Douglas
- Nuclear
Magnetic Resonance Laboratory, University
of Kansas, Lawrence, Kansas 66047, United States
| | - Philip F. Gao
- Protein
Production Group, University of Kansas, Lawrence, Kansas 66047, United States
| | - H. Michael Petrassi
- Calibr,
Scripps Research Institute, La Jolla, California 92037, United States
| | - Michael Zhuo Wang
- Department
of Pharmaceutical Chemistry, University
of Kansas, Lawrence, Kansas 66047, United States
| | - Jingxin Wang
- Department
of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States
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6
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Li YJ, Chen CY, Yang JH, Chiu YF. Modulating cholesterol-rich lipid rafts to disrupt influenza A virus infection. Front Immunol 2022; 13:982264. [PMID: 36177026 PMCID: PMC9513517 DOI: 10.3389/fimmu.2022.982264] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Influenza A virus (IAV) is widely disseminated across different species and can cause recurrent epidemics and severe pandemics in humans. During infection, IAV attaches to receptors that are predominantly located in cell membrane regions known as lipid rafts, which are highly enriched in cholesterol and sphingolipids. Following IAV entry into the host cell, uncoating, transcription, and replication of the viral genome occur, after which newly synthesized viral proteins and genomes are delivered to lipid rafts for assembly prior to viral budding from the cell. Moreover, during budding, IAV acquires an envelope with embedded cholesterol from the host cell membrane, and it is known that decreased cholesterol levels on IAV virions reduce infectivity. Statins are commonly used to inhibit cholesterol synthesis for preventing cardiovascular diseases, and several studies have investigated whether such inhibition can block IAV infection and propagation, as well as modulate the host immune response to IAV. Taken together, current research suggests that there may be a role for statins in countering IAV infections and modulating the host immune response to prevent or mitigate cytokine storms, and further investigation into this is warranted.
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Affiliation(s)
- Yu-Jyun Li
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Yuan Chen
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Jeng-How Yang
- Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, New Taipei, Taiwan
| | - Ya-Fang Chiu
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
- Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
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7
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Shemesh M, Lochte S, Piehler J, Schreiber G. IFNAR1 and IFNAR2 play distinct roles in initiating type I interferon-induced JAK-STAT signaling and activating STATs. Sci Signal 2021; 14:eabe4627. [PMID: 34813358 DOI: 10.1126/scisignal.abe4627] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Maya Shemesh
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Sara Lochte
- Department of Biology and Center of Cellular Nanoanalytics, University of Osnabrück, 49076 Osnabrück, Germany
| | - Jacob Piehler
- Department of Biology and Center of Cellular Nanoanalytics, University of Osnabrück, 49076 Osnabrück, Germany
| | - Gideon Schreiber
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
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8
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Kienes I, Weidl T, Mirza N, Chamaillard M, Kufer TA. Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation. Int J Mol Sci 2021; 22:1301. [PMID: 33525590 PMCID: PMC7865845 DOI: 10.3390/ijms22031301] [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: 12/22/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.
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Affiliation(s)
- Ioannis Kienes
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | - Tanja Weidl
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | - Nora Mirza
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | | | - Thomas A. Kufer
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
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9
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Zanin N, Viaris de Lesegno C, Lamaze C, Blouin CM. Interferon Receptor Trafficking and Signaling: Journey to the Cross Roads. Front Immunol 2021; 11:615603. [PMID: 33552080 PMCID: PMC7855707 DOI: 10.3389/fimmu.2020.615603] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/02/2020] [Indexed: 12/19/2022] Open
Abstract
Like most plasma membrane proteins, type I interferon (IFN) receptor (IFNAR) traffics from the outer surface to the inner compartments of the cell. Long considered as a passive means to simply control subunits availability at the plasma membrane, an array of new evidence establishes IFNAR endocytosis as an active contributor to the regulation of signal transduction triggered by IFN binding to IFNAR. During its complex journey initiated at the plasma membrane, the internalized IFNAR complex, i.e. IFNAR1 and IFNAR2 subunits, will experience post-translational modifications and recruit specific effectors. These finely tuned interactions will determine not only IFNAR subunits destiny (lysosomal degradation vs. plasma membrane recycling) but also the control of IFN-induced signal transduction. Finally, the IFNAR system perfectly illustrates the paradigm of the crosstalk between membrane trafficking and intracellular signaling. Investigating the complexity of IFN receptor intracellular routes is therefore necessary to reveal new insight into the role of IFNAR membrane dynamics in type I IFNs signaling selectivity and biological activity.
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Affiliation(s)
- Natacha Zanin
- NDORMS, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Christine Viaris de Lesegno
- Institut Curie-Centre de Recherche, PSL Research University, Membrane Dynamics and Mechanics of Intracellular Signalling Laboratory, Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.,Centre National de la Recherche Scientifique (CNRS), UMR 3666, Paris, France
| | - Christophe Lamaze
- Institut Curie-Centre de Recherche, PSL Research University, Membrane Dynamics and Mechanics of Intracellular Signalling Laboratory, Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.,Centre National de la Recherche Scientifique (CNRS), UMR 3666, Paris, France
| | - Cedric M Blouin
- Institut Curie-Centre de Recherche, PSL Research University, Membrane Dynamics and Mechanics of Intracellular Signalling Laboratory, Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.,Centre National de la Recherche Scientifique (CNRS), UMR 3666, Paris, France
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10
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Zhou BX, Li J, Liang XL, Pan XP, Hao YB, Xie PF, Jiang HM, Yang ZF, Zhong NS. β-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling. Acta Pharmacol Sin 2020; 41:1178-1196. [PMID: 32504068 PMCID: PMC7273125 DOI: 10.1038/s41401-020-0403-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 03/17/2020] [Indexed: 12/24/2022]
Abstract
β-Sitosterol (24-ethyl-5-cholestene-3-ol) is a common phytosterol Chinese medical plants that has been shown to possess antioxidant and anti-inflammatory activity. In this study we investigated the effects of β-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms. We demonstrate that β-sitosterol (150–450 μg/mL) dose-dependently suppresses inflammatory response through NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells, which was accompanied by decreased induction of interferons (IFNs) (including Type I and III IFN). Furthermore, we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acid-inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon-stimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells. Moreover, β-sitosterol treatment attenuated RIG-I-mediated apoptotic injury of alveolar epithelial cells (AEC) via downregulation of pro-apoptotic factors. In a mouse model of influenza, pre-administration of β-sitosterol (50, 200 mg·kg−1·d−1, i.g., for 2 days) dose-dependently ameliorated IAV-mediated recruitment of pathogenic cytotoxic T cells and immune dysregulation. In addition, pre-administration of β-sitosterol protected mice from lethal IAV infection. Our data suggest that β-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production, providing a potential benefit for the treatment of influenza.
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11
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Kok F, Rosenblatt M, Teusel M, Nizharadze T, Gonçalves Magalhães V, Dächert C, Maiwald T, Vlasov A, Wäsch M, Tyufekchieva S, Hoffmann K, Damm G, Seehofer D, Boettler T, Binder M, Timmer J, Schilling M, Klingmüller U. Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction. Mol Syst Biol 2020; 16:e8955. [PMID: 32696599 PMCID: PMC7373899 DOI: 10.15252/msb.20198955] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 05/29/2020] [Accepted: 06/16/2020] [Indexed: 12/20/2022] Open
Abstract
Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNα) orchestrates antiviral responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNα doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNα signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model-based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNα dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNα leads to a dose-dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient-specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient-specific pathway desensitization, while the abundance of STAT2 predicts the patient-specific IFNα signal response.
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Affiliation(s)
- Frédérique Kok
- Division Systems Biology of Signal TransductionGerman Cancer Research Center (DKFZ)HeidelbergGermany
- Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
| | - Marcus Rosenblatt
- Institute of PhysicsUniversity of FreiburgFreiburgGermany
- FDM ‐ Freiburg Center for Data Analysis and ModelingUniversity of FreiburgFreiburgGermany
| | - Melissa Teusel
- Division Systems Biology of Signal TransductionGerman Cancer Research Center (DKFZ)HeidelbergGermany
- Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
| | - Tamar Nizharadze
- Division Systems Biology of Signal TransductionGerman Cancer Research Center (DKFZ)HeidelbergGermany
- Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
| | - Vladimir Gonçalves Magalhães
- Research Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”Division Virus‐Associated CarcinogenesisGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Christopher Dächert
- Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
- Research Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”Division Virus‐Associated CarcinogenesisGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Tim Maiwald
- Institute of PhysicsUniversity of FreiburgFreiburgGermany
| | - Artyom Vlasov
- Division Systems Biology of Signal TransductionGerman Cancer Research Center (DKFZ)HeidelbergGermany
- Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
| | - Marvin Wäsch
- Division Systems Biology of Signal TransductionGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Silvana Tyufekchieva
- Department of General, Visceral and Transplantation SurgeryRuprecht Karls University HeidelbergHeidelbergGermany
| | - Katrin Hoffmann
- Department of General, Visceral and Transplantation SurgeryRuprecht Karls University HeidelbergHeidelbergGermany
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral TransplantationUniversity of LeipzigLeipzigGermany
| | - Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral TransplantationUniversity of LeipzigLeipzigGermany
| | - Tobias Boettler
- Department of Medicine IIUniversity Hospital Freiburg—Faculty of MedicineUniversity of FreiburgFreiburgGermany
| | - Marco Binder
- Research Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”Division Virus‐Associated CarcinogenesisGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Jens Timmer
- Institute of PhysicsUniversity of FreiburgFreiburgGermany
- FDM ‐ Freiburg Center for Data Analysis and ModelingUniversity of FreiburgFreiburgGermany
- Signalling Research Centres BIOSS and CIBSSUniversity of FreiburgFreiburgGermany
- Center for Biological Systems Analysis (ZBSA)University of FreiburgFreiburgGermany
| | - Marcel Schilling
- Division Systems Biology of Signal TransductionGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Ursula Klingmüller
- Division Systems Biology of Signal TransductionGerman Cancer Research Center (DKFZ)HeidelbergGermany
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12
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Hurtado-Guerrero I, Hernáez B, Pinto-Medel MJ, Calonge E, Rodriguez-Bada JL, Urbaneja P, Alonso A, Mena-Vázquez N, Aliaga P, Issazadeh-Navikas S, Pavia J, Leyva L, Alcamí J, Alcamí A, Fernández Ó, Oliver-Martos B. Antiviral, Immunomodulatory and Antiproliferative Activities of Recombinant Soluble IFNAR2 without IFN-ß Mediation. J Clin Med 2020; 9:jcm9040959. [PMID: 32244308 PMCID: PMC7230527 DOI: 10.3390/jcm9040959] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 03/26/2020] [Accepted: 03/29/2020] [Indexed: 12/21/2022] Open
Abstract
Soluble receptors of cytokines are able to modify cytokine activities and therefore the immune system, and some have intrinsic biological activities without mediation from their cytokines. The soluble interferon beta (IFN-ß) receptor is generated through alternative splicing of IFNAR2 and has both agonist and antagonist properties for IFN-ß, but its role is unknown. We previously demonstrated that a recombinant human soluble IFN-ß receptor showed intrinsic therapeutic efficacy in a mouse model of multiple sclerosis. Here we evaluate the potential biological activities of recombinant sIFNAR2 without the mediation of IFN-ß in human cells. Recombinant sIFNAR2 down-regulated the production of IL-17 and IFN-ɣ and reduced the cell proliferation rate. Moreover, it showed a strong antiviral activity, fully protecting the cell monolayer after being infected by the virus. Specific inhibitors completely abrogated the antiviral activity of IFN-ß, but not that of the recombinant sIFNAR2, and there was no activation of the JAK-STAT signaling pathway. Consequently, r-sIFNAR2 exerts immunomodulatory, antiproliferative and antiviral activities without IFN-ß mediation, and could be a promising treatment against viral infections and immune-mediated diseases.
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Affiliation(s)
- Isaac Hurtado-Guerrero
- Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain; (I.H.-G.); (M.J.P.-M.); (J.L.R.-B.); (P.U.); (A.A.); (N.M.-V.); (P.A.); (J.P.); (L.L.); (Ó.F.)
- UGC Neurociencias. Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
- Red Temática de Investigación Cooperativa: Red Española de Esclerosis Múltiple REEM (RD16/0015/0010), 28049 Madrid, Spain
- Neuroinflammation Unit, Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, Copenhagen Biocentre, University of Copenhagen, 2200 Copenhagen, Denmark;
| | - Bruno Hernáez
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain; (B.H.); (A.A.)
| | - María J. Pinto-Medel
- Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain; (I.H.-G.); (M.J.P.-M.); (J.L.R.-B.); (P.U.); (A.A.); (N.M.-V.); (P.A.); (J.P.); (L.L.); (Ó.F.)
- UGC Neurociencias. Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
- Red Temática de Investigación Cooperativa: Red Española de Esclerosis Múltiple REEM (RD16/0015/0010), 28049 Madrid, Spain
| | - Esther Calonge
- AIDS Immunopathology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda 28220 Madrid, Spain; (E.C.); (J.A.)
| | - José L. Rodriguez-Bada
- Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain; (I.H.-G.); (M.J.P.-M.); (J.L.R.-B.); (P.U.); (A.A.); (N.M.-V.); (P.A.); (J.P.); (L.L.); (Ó.F.)
- UGC Neurociencias. Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
- Red Temática de Investigación Cooperativa: Red Española de Esclerosis Múltiple REEM (RD16/0015/0010), 28049 Madrid, Spain
| | - Patricia Urbaneja
- Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain; (I.H.-G.); (M.J.P.-M.); (J.L.R.-B.); (P.U.); (A.A.); (N.M.-V.); (P.A.); (J.P.); (L.L.); (Ó.F.)
- UGC Neurociencias. Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
- Red Temática de Investigación Cooperativa: Red Española de Esclerosis Múltiple REEM (RD16/0015/0010), 28049 Madrid, Spain
| | - Ana Alonso
- Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain; (I.H.-G.); (M.J.P.-M.); (J.L.R.-B.); (P.U.); (A.A.); (N.M.-V.); (P.A.); (J.P.); (L.L.); (Ó.F.)
- UGC Neurociencias. Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
- Red Temática de Investigación Cooperativa: Red Española de Esclerosis Múltiple REEM (RD16/0015/0010), 28049 Madrid, Spain
| | - Natalia Mena-Vázquez
- Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain; (I.H.-G.); (M.J.P.-M.); (J.L.R.-B.); (P.U.); (A.A.); (N.M.-V.); (P.A.); (J.P.); (L.L.); (Ó.F.)
- UGC de Reumatología, Hospital Regional Universitario de Málaga, 29009 Málaga, Spain
| | - Pablo Aliaga
- Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain; (I.H.-G.); (M.J.P.-M.); (J.L.R.-B.); (P.U.); (A.A.); (N.M.-V.); (P.A.); (J.P.); (L.L.); (Ó.F.)
- UGC Neurociencias. Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - Shohreh Issazadeh-Navikas
- Neuroinflammation Unit, Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, Copenhagen Biocentre, University of Copenhagen, 2200 Copenhagen, Denmark;
| | - José Pavia
- Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain; (I.H.-G.); (M.J.P.-M.); (J.L.R.-B.); (P.U.); (A.A.); (N.M.-V.); (P.A.); (J.P.); (L.L.); (Ó.F.)
- Departamento de Farmacología y Pediatría, Facultad de Medicina. Universidad de Málaga, 29010 Málaga, Spain
| | - Laura Leyva
- Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain; (I.H.-G.); (M.J.P.-M.); (J.L.R.-B.); (P.U.); (A.A.); (N.M.-V.); (P.A.); (J.P.); (L.L.); (Ó.F.)
- UGC Neurociencias. Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
- Red Temática de Investigación Cooperativa: Red Española de Esclerosis Múltiple REEM (RD16/0015/0010), 28049 Madrid, Spain
| | - José Alcamí
- AIDS Immunopathology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda 28220 Madrid, Spain; (E.C.); (J.A.)
- HIV Unit, Infectious Disease Service, Hospital Universitari de Bellvitge, 08907 Barcelona, Spain
| | - Antonio Alcamí
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain; (B.H.); (A.A.)
| | - Óscar Fernández
- Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain; (I.H.-G.); (M.J.P.-M.); (J.L.R.-B.); (P.U.); (A.A.); (N.M.-V.); (P.A.); (J.P.); (L.L.); (Ó.F.)
- Departamento de Farmacología y Pediatría, Facultad de Medicina. Universidad de Málaga, 29010 Málaga, Spain
| | - Begoña Oliver-Martos
- Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain; (I.H.-G.); (M.J.P.-M.); (J.L.R.-B.); (P.U.); (A.A.); (N.M.-V.); (P.A.); (J.P.); (L.L.); (Ó.F.)
- UGC Neurociencias. Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
- Red Temática de Investigación Cooperativa: Red Española de Esclerosis Múltiple REEM (RD16/0015/0010), 28049 Madrid, Spain
- Correspondence: ; Tel.: +34-951-290-223
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Anjum FR, Rahman SU, Aslam MA, Qureshi AS. Comprehensive network map of transcriptional activation of chicken type I IFNs and IFN-stimulated genes. Comp Immunol Microbiol Infect Dis 2019; 68:101407. [PMID: 31877494 DOI: 10.1016/j.cimid.2019.101407] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 12/04/2019] [Accepted: 12/16/2019] [Indexed: 01/04/2023]
Abstract
Chicken type I interferons (type I IFNs) are key antiviral players of the chicken immune system and mediate the first line of defense against viral pathogens infecting the avian species. Recognition of viral pathogens by specific pattern recognition receptors (PRRs) induce chicken type I IFNs expression followed by their subsequent interaction to IFN receptors and induction of a variety of IFN stimulated antiviral proteins. These antiviral effectors establish the antiviral state in neighboring cells and thus protect the host from infection. Three subtypes of chicken type I IFNs; chIFN-α, chIFN-β, and a recently discovered chIFN-κ have been identified and characterized in chicken. Chicken type I IFNs are activated by various host cell pathways and constitute a major antiviral innate defense in chicken. This review will help to understand the chicken type 1 IFNs, host cellular pathways that are involved in activation of chicken type I IFNs and IFN stimulated antiviral effectors along with the gaps in knowledge which will be important for future investigation. These findings will help us to comprehend the role of chicken type I IFNs and to develop different strategies for controlling viral infection in poultry.
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Affiliation(s)
| | - Sajjad Ur Rahman
- Institute of Microbiology, University of Agriculture, Faisalabad, Pakistan
| | | | - Anas Sarwar Qureshi
- Department of Anatomy, Faculty of Veterinary Science, University of Agriculture, Faisalabad, Pakistan
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Talebi S, Saeedinia A, Zeinoddini M, Ahmadpour F, Sadeghizadeh M. Evaluation of a single amino acid substitution at position 79 of human IFN-α2b in interferon-receptor assembly and activity. Prep Biochem Biotechnol 2019; 49:735-743. [PMID: 31135267 DOI: 10.1080/10826068.2019.1566143] [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: 10/26/2022]
Abstract
Type I interferons (IFNs) are homologous cytokines that bind to a cell surface receptor and establish signaling pathways that motivate immune responses. The purpose of the current study is to assess the activity of a novel-engineered IFN-α2b. The crystallographic structure of IFN-α2b and its receptors was acquired from Protein Data Bank. Various amino acid substitutions were designed based on structural properties and other biological characteristics of residues to find the most effective amino acid on IFN affinity to advanced activities. The IFN-α2b mutants and receptors have been modeled and the interactions between two proteins have been studied as in silico by protein-protein docking for both mutants and native forms. The proper nucleic acid sequence IFN-α2 (T79Q) has been prepared based on the selected mutant. The modified IFN gene was cloned in pcDNA 3.1(-) and introduced to Chinese Hamster Ovary (CHO) cell line. Antiviral and antiproliferative assays of native and IFN-α2 (T79Q) proteins were performed in vitro. The results showed two-fold increasing in IFN-α2 (T79Q) activity (antiviral and antiproliferative activity) in comparison to native IFN-α2b. This engineered IFN-α2b may have significant novel therapeutic applications and in silico studies can be an influential method for practical research function and structure of these molecules.
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Affiliation(s)
- Samira Talebi
- a Malek Ashtar University of Technology , Tehran , Iran.,b Trauma Research Centre, Baqiyatallah University of Medical Sciences , Tehran , Iran
| | | | | | - Fathollah Ahmadpour
- b Trauma Research Centre, Baqiyatallah University of Medical Sciences , Tehran , Iran
| | - Majid Sadeghizadeh
- c Department of Genetics, School of Biological Sciences, Tarbiat Modares University , Tehran , Iran
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15
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Shah M, Bharadwaj MSK, Gupta A, Kumar R, Kumar S. Chicken viperin inhibits Newcastle disease virus infection in vitro: A possible interaction with the viral matrix protein. Cytokine 2019; 120:28-40. [PMID: 31003187 DOI: 10.1016/j.cyto.2019.04.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 03/28/2019] [Accepted: 04/12/2019] [Indexed: 02/06/2023]
Abstract
Viperin is an interferon-inducible protein that helps in protecting mammals against various virus infections. Viperin is a highly conserved member of the interferon-stimulated genes (ISG) family in many species. Viperin has been shown to play a pivotal role in the innate immunity of chicken; however, its role has not been explored in its antiviral potential. Newcastle disease virus (NDV) is the causative agent of an infectious disease in poultry. In the present study, we have shown the anti-NDV effect of chicken viperin (cViperin). The impact of cViperin upon NDV infection was investigated in chicken embryo fibroblast. The modeling of the cViperin protein was done using I-TASSER and ZDOCK is used to predict the possible interaction with the matrix protein of NDV. The interaction was further confirmed by co-immunoprecipitation assay using recombinant matrix protein of NDV with the recombinant cViperin. The recombinant NDV expressing cViperin showed reduced replication of the virus upon its growth kinetics. Our results suggest downregulation of NDV replication in the presence of cViperin. The study will be critical to elaborate our understanding of the chicken innate immune system which could help develop antiviral strategies against NDV infection.
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Affiliation(s)
- Manisha Shah
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - M S K Bharadwaj
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Anjali Gupta
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Rakesh Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Sachin Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
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16
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Ahmed-Hassan H, Abdul-Cader MS, Ahmed Sabry M, Hamza E, Sharif S, Nagy E, Abdul-Careem MF. Double-Stranded Ribonucleic Acid-Mediated Antiviral Response Against Low Pathogenic Avian Influenza Virus Infection. Viral Immunol 2018; 31:433-446. [PMID: 29813000 DOI: 10.1089/vim.2017.0142] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Toll-like receptor (TLR)3 signaling pathway is known to induce type 1 interferons (IFNs) and proinflammatory mediators leading to antiviral response against many viral infections. Double-stranded ribonucleic acid (dsRNA) has been shown to act as a ligand for TLR3 and, as such, has been a focus as a potential antiviral agent in many host-viral infection models. Yet, its effectiveness and involved mechanisms as a mediator against low pathogenic avian influenza virus (LPAIV) have not been investigated adequately. In this study, we used avian fibroblasts to verify whether dsRNA induces antiviral response against H4N6 LPAIV and clarify whether type 1 IFNs and proinflammatory mediators such as interleukin (IL)-1β are contributing to the dsRNA-mediated antiviral response against H4N6 LPAIV. We found that dsRNA induces antiviral response in avian fibroblasts against H4N6 LPAIV infection. The treatment of avian fibroblasts with dsRNA increases the expressions of TLR3, IFN-α, IFN-β, and IL-1β. We also confirmed that this antiviral response elicited against H4N6 LPAIV infection correlates, but is not attributable to type 1 IFNs or IL-1β. Our findings imply that the TLR3 ligand, dsRNA, can elicit antiviral response in avian fibroblasts against LPAIV infection, highlighting potential value of dsRNA as an antiviral agent against LPAIV infections. However, further investigations are required to determine the potential role of other innate immune mediators or combination of the tested cytokines in the dsRNA-mediated antiviral response against H4N6 LPAIV infection.
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Affiliation(s)
- Hanaa Ahmed-Hassan
- 1 Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, Health Research Innovation Center 2C53, University of Calgary , Calgary, Alberta, Canada .,2 Zoonoses Department, Faculty of Veterinary Medicine, Cairo University , Giza, Egypt
| | - Mohamed Sarjoon Abdul-Cader
- 1 Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, Health Research Innovation Center 2C53, University of Calgary , Calgary, Alberta, Canada
| | - Maha Ahmed Sabry
- 2 Zoonoses Department, Faculty of Veterinary Medicine, Cairo University , Giza, Egypt
| | - Eman Hamza
- 2 Zoonoses Department, Faculty of Veterinary Medicine, Cairo University , Giza, Egypt
| | - Shayan Sharif
- 3 Department of Pathobiology, University of Guelph , Guelph, Ontario, Canada
| | - Eva Nagy
- 3 Department of Pathobiology, University of Guelph , Guelph, Ontario, Canada
| | - Mohamed Faizal Abdul-Careem
- 1 Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, Health Research Innovation Center 2C53, University of Calgary , Calgary, Alberta, Canada
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17
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Ahmed-Hassan H, Abdul-Cader MS, De Silva Senapathi U, Sabry MA, Hamza E, Nagy E, Sharif S, Abdul-Careem MF. Potential mediators of in ovo delivered double stranded (ds) RNA-induced innate response against low pathogenic avian influenza virus infection. Virol J 2018. [PMID: 29530062 PMCID: PMC5848551 DOI: 10.1186/s12985-018-0954-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Toll like receptor (TLR) 3 is a critically important innate pattern recognizing receptor that senses many viral infections. Although, it has been shown that double stranded (ds) RNA can be used for the stimulation of TLR3 signaling pathway in a number of host-viral infection models, it’s effectiveness as an antiviral agent against low pathogenic avian influenza virus (LPAIV) needs further investigation. Methods In this study, first, we delivered TLR3 ligand, dsRNA, in ovo at embryo day (ED)18 since in ovo route is routinely used for vaccination against poultry viral and parasitic infections and infected with H4N6 LPAIV 24-h post-treatment. A subset of in ovo dsRNA treated and control groups were observed for the expressions of TLR3 and type I interferon (IFN)s, mRNA expression of interleukin (IL)-1β and macrophage recruitment coinciding with the time of H4N6 LPAIV infection (24 h post-treatment). Additionally, Day 1 chickens were given dsRNA intra-tracheally along with a control group and a subset of chickens were infected with H4N6 LPAIV 24-h post-treatment whereas the rest of the animals were observed for macrophage and type 1 IFN responses coinciding with the time of viral infection. Results Our results demonstrate that the pre-hatch treatment of eggs with dsRNA reduces H4N6 replication in lungs. Further studies revealed that in ovo delivery of dsRNA increases TLR3 expression, type I IFN production and number of macrophages in addition to mRNA expression of IL-1β in lung 24-h post-treatment. The same level of induction of innate response was not evident in the spleen. Moreover, we discovered that dsRNA elicits antiviral response against LPAIV correlating with type I IFN activity in macrophages in vitro. Post-hatch, we found no difference in H4N6 LPAIV genome loads between dsRNA treated and control chickens although we observed higher macrophage recruitment and IFN-β response coinciding with the time of viral infection. Conclusions Our findings imply that the TLR3 ligand, dsRNA has antiviral activity in ovo and in vitro but not in chickens post-hatch and dsRNA-mediated innate host response is characterized by macrophage recruitment and expressions of TLR3 and type 1 IFNs.
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Affiliation(s)
- Hanaa Ahmed-Hassan
- Department of Ecosystem and Public Health, University of Calgary, Health Research Innovation Center 2C53, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.,Zoonoses Department, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
| | - Mohamed Sarjoon Abdul-Cader
- Department of Ecosystem and Public Health, University of Calgary, Health Research Innovation Center 2C53, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Upasama De Silva Senapathi
- Department of Ecosystem and Public Health, University of Calgary, Health Research Innovation Center 2C53, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Maha Ahmed Sabry
- Zoonoses Department, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
| | - Eman Hamza
- Zoonoses Department, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
| | - Eva Nagy
- Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Shayan Sharif
- Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Mohamed Faizal Abdul-Careem
- Department of Ecosystem and Public Health, University of Calgary, Health Research Innovation Center 2C53, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
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Kasmapour B, Kubsch T, Rand U, Eiz-Vesper B, Messerle M, Vondran FWR, Wiegmann B, Haverich A, Cicin-Sain L. Myeloid Dendritic Cells Repress Human Cytomegalovirus Gene Expression and Spread by Releasing Interferon-Unrelated Soluble Antiviral Factors. J Virol 2018; 92:e01138-17. [PMID: 29046460 PMCID: PMC5730771 DOI: 10.1128/jvi.01138-17] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 10/03/2017] [Indexed: 12/21/2022] Open
Abstract
Cytomegalovirus (CMV) is a betaherpesvirus that latently infects most adult humans worldwide and is a major cause of morbidity and mortality in immunocompromised hosts. Latent human CMV (HCMV) is believed to reside in precursors of myeloid-lineage leukocytes and monocytes, which give rise to macrophages and dendritic cells (DC). We report here that human monocyte-derived DC (mo-DC) suppress HCMV infection in coculture with infected fibroblast target cells in a manner dependent on the effector-to-target ratio. Intriguingly, optimal activation of mo-DC was achieved under coculture conditions and not by direct infection with HCMV, implying that mo-DC may recognize unique molecular patterns on, or within, infected fibroblasts. We show that HCMV is controlled by secreted factors that act by priming defenses in target cells rather than by direct viral neutralization, but we excluded a role for interferons (IFNs) in this control. The expression of lytic viral genes in infected cells and the progression of infection were significantly slowed, but this effect was reversible, indicating that the control of infection depended on the transient induction of antiviral effector molecules in target cells. Using immediate early or late-phase reporter HCMVs, we show that soluble factors secreted in the cocultures suppress HCMV replication at both stages of the infection and that their antiviral effects are robust and comparable in numerous batches of mo-DC as well as in primary fibroblasts and stromal cells.IMPORTANCE Human cytomegalovirus is a widespread opportunistic pathogen that can cause severe disease and complications in vulnerable individuals. This includes newborn children, HIV AIDS patients, and transplant recipients. Although the majority of healthy humans carry this virus throughout their lives without symptoms, it is not exactly clear which tissues in the body are the main reservoirs of latent virus infection or how the delicate balance between the virus and the immune system is maintained over an individual's lifetime. Here, for the first time, we provide evidence for a novel mechanism of direct virus control by a subset of human innate immune cells called dendritic cells, which are regarded as a major site of virus latency and reactivation. Our findings may have important implications in HCMV disease prevention as well as in development of novel therapeutic approaches.
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Affiliation(s)
- Bahram Kasmapour
- Immune Ageing and Chronic Infections Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Tobias Kubsch
- Immune Ageing and Chronic Infections Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Ulfert Rand
- Immune Ageing and Chronic Infections Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Britta Eiz-Vesper
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Martin Messerle
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Florian W R Vondran
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research, Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Bettina Wiegmann
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Axel Haverich
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Luka Cicin-Sain
- Immune Ageing and Chronic Infections Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Institute of Virology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research, Partner Site Hannover-Braunschweig, Braunschweig, Germany
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Chicken IFN Kappa: A Novel Cytokine with Antiviral Activities. Sci Rep 2017; 7:2719. [PMID: 28578423 PMCID: PMC5457445 DOI: 10.1038/s41598-017-02951-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 04/25/2017] [Indexed: 12/24/2022] Open
Abstract
Interferons (IFNs) are essential components of the host innate immune system and define first-line of defence against pathogens. In mammals, several type I IFNs are identified, however, only limited data is available on the repertoire of IFNs in avian species. Here we report the characterization of chicken IFN-κ (chIFN-κ) near the type I IFN locus on the sex-determining Z chromosome. Genetic, evolutionary and syntenic analyses indicate that chIFN-κ is a type I IFN with conserved genetic features and promoter binding sites. chIFN-κ regulated the IFN-stimulated response element signalling pathways and activated a panel of IFN-regulated genes, antiviral mediators and transcriptional regulators. Priming of chicken primary fibroblasts and tracheal organ cultures with chIFN-κ imparted cellular protections against viral infections both in vitro and ex vivo. To determine whether chIFN-κ defines the antiviral state in developing chicken embryos, we used replication-competent retroviral RCAS vector system to generate transgenic chicken embryos that constitutively and stably expressed chIFN-κ. We could demonstrate that chIFN-κ markedly inhibited the replication of avian RNA viruses in ovo. Collectively, these results shed the light on the repertoire of IFNs in avian species and provide functional data on the interaction of the chIFN-κ with RNA viruses of poultry and public health importance.
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20
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Retraction notice. Muscle Nerve 2017; 55:766. [DOI: 10.1002/mus.21394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Recombinant soluble IFN receptor (sIFNAR2) exhibits intrinsic therapeutic efficacy in a murine model of Multiple Sclerosis. Neuropharmacology 2016; 110:480-492. [DOI: 10.1016/j.neuropharm.2016.07.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 07/19/2016] [Accepted: 07/20/2016] [Indexed: 11/23/2022]
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Órpez-Zafra T, Pavía J, Hurtado-Guerrero I, Pinto-Medel MJ, Rodriguez Bada JL, Urbaneja P, Suardíaz M, Villar LM, Comabella M, Montalban X, Alvarez-Cermeño JC, Leyva L, Fernández Ó, Oliver-Martos B. Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Mult Scler 2016; 23:937-945. [DOI: 10.1177/1352458516667564] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Background: The soluble isoform of the interferon-β (IFN-β) receptor (sIFNAR2) could modulate the activity of both endogenous and systemically administered IFN-β. Previously, we described lower serum sIFNAR2 levels in untreated multiple sclerosis (MS) than in healthy controls (HCs). Objective: To assess sIFNAR2 levels in a new cohort of MS patients and HCs, as well as in patients with clinically isolated syndrome (CIS) and with other inflammatory neurological disorders (OIND) and to assess its ability as a diagnostic biomarker. Methods: The cross-sectional study included 148 MS (84 treatment naive and 64 treated), 87 CIS, 42 OIND, and 96 HCs. Longitudinal study included 94 MS pretreatment and after 1 year of therapy with IFN-β, glatiramer acetate (GA), or natalizumab. sIFNAR2 serum levels were measured by a quantitative ELISA developed and validated in our laboratory. Results: Naive MS and CIS patients showed significantly lower sIFNAR2 levels than HCs and OIND patients. The sensitivity and specificity to discriminate between MS and OIND, for a sIFNAR2 cutoff value of 122.02 ng/mL, were 70.1%, and 79.4%, respectively. sIFNAR2 increased significantly in IFN-β-treated patients during the first year of therapy in contrast to GA- and natalizumab-treated patients who showed non-significant changes. Conclusion: The results suggest that sIFNAR2 could be a potential diagnostic biomarker for MS.
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Affiliation(s)
- Teresa Órpez-Zafra
- Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Jose Pavía
- Departamento de Farmacología y Pediatría, Facultad de Medicina, Instituto de Biomedicina de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain
| | - Isaac Hurtado-Guerrero
- Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Maria J Pinto-Medel
- Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain/Red Española de Esclerosis Múltiple (REEM)
| | - Jose Luis Rodriguez Bada
- Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Patricia Urbaneja
- Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Margarita Suardíaz
- Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain/Red Española de Esclerosis Múltiple (REEM)
| | - Luisa M Villar
- Servicio de Inmunología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain/Red Española de Esclerosis Múltiple (REEM)
| | - Manuel Comabella
- Department de Neurología-Neuroinmunología, Centre d’Esclerosi Múltiple de Catalunya, Vall d’Hebron Institut de Recerca, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain/Red Española de Esclerosis Múltiple (REEM)
| | - Xavier Montalban
- Department de Neurología-Neuroinmunología, Centre d’Esclerosi Múltiple de Catalunya, Vall d’Hebron Institut de Recerca, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain/Red Española de Esclerosis Múltiple (REEM)
| | - Jose C Alvarez-Cermeño
- Servicio de Neurología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain/Red Española de Esclerosis Múltiple (REEM)
| | - Laura Leyva
- Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain/Red Española de Esclerosis Múltiple (REEM)
| | - Óscar Fernández
- Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain/Red Española de Esclerosis Múltiple (REEM)
| | - Begoña Oliver-Martos
- Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain/Red Española de Esclerosis Múltiple (REEM)
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23
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Galani V, Kastamoulas M, Varouktsi A, Lampri E, Mitselou A, Arvanitis DL. IFNs-signaling effects on lung cancer: an up-to-date pathways-specific review. Clin Exp Med 2016; 17:281-289. [PMID: 27416926 DOI: 10.1007/s10238-016-0432-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 07/07/2016] [Indexed: 01/01/2023]
Abstract
IFNs have found important applications in clinical medicine, including the treatment of lung malignancies. The biological effect of the IFN-receptor signaling is regulated essentially by three factors: the expression profile of the IFN itself, the profile of the receptor, and the expression of target genes. IFNs initiate their signaling by binding to specific receptors. The activated IFNs can directly induce gene transcription and/or multiple downstream signaling that both induce diverse cellular responses including the cell cycle arrest and the apoptosis in tumor cells. We provided evidence that IFN-γ enhances the pro cell death effects of Fas/CD95 in human neoplastic alveolar epithelial cell line, A549. We also found that p27 protein plays a pivotal role in the inducing cell death of IFNγ-CH-11-treated A549 cells, since it is involved in the Ras/Raf signaling pathway. This article discusses recent insights into these possible additional functions of IFNs in lung cancer treatment.
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Affiliation(s)
- Vasiliki Galani
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, University of Ioannina, 45110, Ioannina, Greece.
| | - Michalis Kastamoulas
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, University of Ioannina, 45110, Ioannina, Greece
| | | | - Evangeli Lampri
- Department of Cancer Biobank Center, University of Ioannina, Ioannina, Greece
| | - Antigoni Mitselou
- Department of Forensic Pathology, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Dimitrios L Arvanitis
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, University of Thessaly, Larissa, Greece
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24
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Magiri RB, Lai K, Chaffey AM, Wilson HL, Berry WE, Szafron ML, Mutwiri GK. Response of immune response genes to adjuvants poly [di(sodium carboxylatoethylphenoxy)phosphazene] (PCEP), CpG oligodeoxynucleotide and emulsigen at intradermal injection site in pigs. Vet Immunol Immunopathol 2016; 175:57-63. [PMID: 27269793 DOI: 10.1016/j.vetimm.2016.05.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 04/27/2016] [Accepted: 05/05/2016] [Indexed: 01/24/2023]
Abstract
Understanding the mechanisms by which adjuvants mediate their effects provide critical information on how innate immunity influences the development of adaptive immunity. Despite being a critical vaccine component, the mechanisms by which adjuvants mediate their effects are not fully understood and this is especially true when they are used in large animals. This lack of understanding limits our ability to design effective vaccines. In the present study, we administered polyphosphazene (PCEP), CpG oligodeoxynucleotides (CpG), emulsigen or saline via an intradermal injection into pigs and assessed the impact on the expression of reported 'adjuvant response genes' over time. CpG induced a strong upregulation of the chemokine CXL10 several 'Interferon Response Genes', as well as TNFα, and IL-10, and a down-regulation of IL-17 genes. Emulsigen upregulated expression of chemokines CCL2 and CCL5, proinflammatory cytokines IL-6 and TNFα, as well as TLR9, and several IFN response genes. PCEP induced the expression of chemokine CCL2 and proinflammatory cytokine IL-6. These results suggest that emulsigen and CpG may promote recruitment of innate immune cells and Th1 type cytokine production but that PCEP may promote a Th-2 type immune response through the induction of IL-6, an inducer of B cell activity and differentiation.
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Affiliation(s)
- R B Magiri
- Vaccinology & Immunotherapeutic Program, School of Public Health at the University of Saskatchewan, Vaccine & Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), 120 Veterinary Road, S7N 5E3 Saskatoon, Saskatchewan, Canada.
| | - K Lai
- Vaccinology & Immunotherapeutic Program, School of Public Health at the University of Saskatchewan, Vaccine & Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), 120 Veterinary Road, S7N 5E3 Saskatoon, Saskatchewan, Canada.
| | - A M Chaffey
- Vaccinology & Immunotherapeutic Program, School of Public Health at the University of Saskatchewan, Vaccine & Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), 120 Veterinary Road, S7N 5E3 Saskatoon, Saskatchewan, Canada
| | - H L Wilson
- Vaccinology & Immunotherapeutic Program, School of Public Health at the University of Saskatchewan, Vaccine & Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), 120 Veterinary Road, S7N 5E3 Saskatoon, Saskatchewan, Canada.
| | - W E Berry
- Vaccinology & Immunotherapeutic Program, School of Public Health at the University of Saskatchewan, Vaccine & Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), 120 Veterinary Road, S7N 5E3 Saskatoon, Saskatchewan, Canada.
| | - M L Szafron
- Vaccinology & Immunotherapeutic Program, School of Public Health at the University of Saskatchewan, Vaccine & Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), 120 Veterinary Road, S7N 5E3 Saskatoon, Saskatchewan, Canada.
| | - G K Mutwiri
- Vaccinology & Immunotherapeutic Program, School of Public Health at the University of Saskatchewan, Vaccine & Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), 120 Veterinary Road, S7N 5E3 Saskatoon, Saskatchewan, Canada.
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25
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Interferon Beta: From Molecular Level to Therapeutic Effects. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2016; 326:343-72. [DOI: 10.1016/bs.ircmb.2016.06.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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26
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Wei L, Bello AM, Majchrzak-Kita B, Salum N, Lewis MM, Kotra LP, Fish EN. Small Molecule Agonists for the Type I Interferon Receptor: An In Silico Approach. J Interferon Cytokine Res 2015; 36:180-91. [PMID: 26700737 DOI: 10.1089/jir.2015.0123] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Type I interferons (IFNs) exhibit broad-spectrum antiviral activity, with potential utility against emerging acute virus infections that pose a threat to global health. Recombinant IFN-αs that have been approved for clinical use require cold storage and are administered through intramuscular or subcutaneous injection, features that are problematic for global distribution, storage, and administration. Cognizant that the biological potency of an IFN-α subtype is determined by its binding affinity to the type I IFN receptor, IFNAR, we identified a panel of small molecule nonpeptide compounds using an in silico screening strategy that incorporated specific structural features of amino acids in the receptor-binding domains of the most potent IFN-α, IFN alfacon-1. Hit compounds were selected based on ease of synthesis and formulation properties. In preliminary biological assays, we provide evidence that these compounds exhibit antiviral activity. This proof-of-concept study validates the strategy of in silico design and development for IFN mimetics.
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Affiliation(s)
- Lianhu Wei
- 1 Center for Molecular Design and Preformulations , Toronto, Canada .,2 Toronto General Research Institute, University Health Network , Toronto, Canada .,3 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Canada
| | - Angelica M Bello
- 1 Center for Molecular Design and Preformulations , Toronto, Canada .,2 Toronto General Research Institute, University Health Network , Toronto, Canada .,3 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Canada
| | - Beata Majchrzak-Kita
- 2 Toronto General Research Institute, University Health Network , Toronto, Canada
| | - Noruê Salum
- 1 Center for Molecular Design and Preformulations , Toronto, Canada .,4 Federal University of Paraná , Paraná, Brazil
| | - Melissa M Lewis
- 1 Center for Molecular Design and Preformulations , Toronto, Canada .,2 Toronto General Research Institute, University Health Network , Toronto, Canada
| | - Lakshmi P Kotra
- 1 Center for Molecular Design and Preformulations , Toronto, Canada .,2 Toronto General Research Institute, University Health Network , Toronto, Canada .,3 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Canada
| | - Eleanor N Fish
- 2 Toronto General Research Institute, University Health Network , Toronto, Canada .,5 Department of Immunology, Faculty of Medicine, University of Toronto , Toronto, Canada
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27
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Development and validation of an ELISA for quantification of soluble IFN-β receptor: assessment in multiple sclerosis. Bioanalysis 2015; 7:2869-80. [DOI: 10.4155/bio.15.208] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Aim: The soluble isoform of the IFN-β receptor (sIFNAR2) can bind IFN-β and modulate its activity, although its role in autoimmune diseases remains unknown. Methods: A recombinant human sIFNAR2 protein was cloned, expressed and purified after which we developed and validated an ELISA for its quantification in human serum. Serum sIFNAR2 were assessed in multiple sclerosis (MS) patients and healthy controls. Results: The ELISA has a dynamic range of 3.9–250 ng/ml and a detection limit of 2.44 ng/ml. Serum sIFNAR2 were significantly lower in untreated-MS patients than in healthy controls. Conclusion: The ELISA is suitable for quantification of sIFNAR2 in serum and should facilitate the study of sIFNAR2 in neuroimmunological diseases such as MS.
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28
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Rahman MM, Uyangaa E, Han YW, Hur J, Park SY, Lee JH, Kim K, Eo SK. Modulation of systemic and mucosal immunity against an inactivated vaccine of Newcastle disease virus by oral co-administration of live attenuated Salmonella enterica serovar Typhimurium expressing chicken interleukin-18 and interferon-α. J Vet Med Sci 2014; 77:395-403. [PMID: 25502364 PMCID: PMC4427739 DOI: 10.1292/jvms.14-0495] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Newcastle disease (ND) is a highly contagious disease of chickens causing significant
economic losses worldwide. Due to limitations in the efficacy against currently
circulating ND viruses, existing vaccination strategies require improvements, and
incorporating immunomodulatory cytokines with existing vaccines might be a novel approach.
Here, we investigated the systemic and mucosal immunomodulatory properties of oral
co-administration of chicken interleukin-18 (chIL-18) and chicken interferon-α (chIFN-α)
using attenuated Salmonella enterica serovar Typhimurium on an
inactivated ND vaccine. Our results demonstrate that oral administration of S.
enterica serovar Typhimurium expressing chIL-18 or chIFN-α provided enhanced
systemic and mucosal immune responses, as determined by serum hemagglutination inhibition
antibody and NDV Ag-specific IgG as well as NDV Ag-specific IgA in lung and duodenal
lavages of chickens immunized with inactivated ND vaccine via the intramuscular or
intranasal route. Notably, combined oral administration of S. enterica
serovar Typhimurium expressing chIL-18 and chIFN-α significantly enhanced systemic and
mucosal immunity in ND-vaccinated chickens, compared to single administration of
S. enterica serovar Typhimurium expressing chIL-18 or chIFN-α. In
addition, oral co-administration of S. enterica serovar Typhimurium
expressing chIL-18 and chIFN-α provided enhanced NDV Ag-specific proliferation of
peripheral blood mononuclear cells and Th1-biased cell-mediated immunity, compared to
single administration of either construct. Therefore, our results provide valuable insight
into the modulation of systemic and mucosal immunity by incorporation of immunomodulatory
chIL-18 and chIFN-α using Salmonella vaccines into existing ND
vaccines.
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Affiliation(s)
- Md Masudur Rahman
- College of Veterinary and Bio-Safety Research Institute, Chonbuk National University, Jeonju 561-756, Republic of Korea; Faculty of Veterinary and Animal Science, Sylhet Agricultural University, Sylhet 3100, Bangladesh
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29
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Samarajiwa SA, Mangan NE, Hardy MP, Najdovska M, Dubach D, Braniff SJ, Owczarek CM, Hertzog PJ. Soluble IFN receptor potentiates in vivo type I IFN signaling and exacerbates TLR4-mediated septic shock. THE JOURNAL OF IMMUNOLOGY 2014; 192:4425-35. [PMID: 24696235 DOI: 10.4049/jimmunol.1302388] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Circulating levels of a soluble type I IFNR are elevated in diseases, such as chronic inflammation, infections, and cancer, but whether it functions as an antagonist, agonist, or transporter is unknown. In this study, we elucidate the in vivo importance of the soluble type I IFNAR, soluble (s)IFNAR2a, which is generated by alternative splicing of the Ifnar2 gene. A transgenic mouse model was established to mimic the 10-15-fold elevated expression of sIFNAR2a observed in some human diseases. We generated transgenic mouse lines, designated SolOX, in which the transgene mRNA and protein-expression patterns mirrored the expression patterns of the endogenous gene. SolOX were demonstrated to be more susceptible to LPS-mediated septic shock, a disease model in which type I IFN plays a crucial role. This effect was independent of "classical" proinflammatory cytokines, such as TNF-α and IL-6, whose levels were unchanged. Because the increased levels of sIFNAR2a did not affect the kinetics of the increased interferonemia, this soluble receptor does not potentiate its ligand signaling by improving IFN pharmacokinetics. Mechanistically, increased levels of sIFNAR2a are likely to facilitate IFN signaling, as demonstrated in spleen cells overexpressing sIFNAR2a, which displayed quicker, higher, and more sustained activation of STAT1 and STAT3. Thus, the soluble IFNR is an important agonist of endogenous IFN actions in pathophysiological processes and also is likely to modulate the therapeutic efficacy of clinically administered IFNs.
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Affiliation(s)
- Shamith A Samarajiwa
- Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia
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30
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Dicitore A, Caraglia M, Gaudenzi G, Manfredi G, Amato B, Mari D, Persani L, Arra C, Vitale G. Type I interferon-mediated pathway interacts with peroxisome proliferator activated receptor-γ (PPAR-γ): at the cross-road of pancreatic cancer cell proliferation. Biochim Biophys Acta Rev Cancer 2013; 1845:42-52. [PMID: 24295567 DOI: 10.1016/j.bbcan.2013.11.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 11/14/2013] [Accepted: 11/22/2013] [Indexed: 12/12/2022]
Abstract
Pancreatic adenocarcinoma remains an unresolved therapeutic challenge because of its intrinsically refractoriness to both chemo- and radiotherapy due to the complexity of signaling and the activation of survival pathways in cancer cells. Recent studies have demonstrated that the combination of some drugs, targeting most of aberrant pathways crucial for the survival of pancreatic cancer cells may be a valid antitumor strategy for this cancer. Type I interferons (IFNs) may have a role in the pathogenesis and progression of pancreatic adenocarcinoma, but the limit of their clinical use is due to the activation of tumor resistance mechanisms, including JAK-2/STAT-3 pathway. Moreover, aberrant constitutive activation of STAT-3 proteins has been frequently detected in pancreatic adenocarcinoma. The selective targeting of these cell survival cascades could be a promising strategy in order to enhance the antitumor effects of type I IFNs. The activation of peroxisome proliferator-activated receptor γ (PPAR-γ), on the other hand, has a suppressive activity on STAT-3. In fact, PPAR-γ agonists negatively modulate STAT-3 through direct and/or indirect mechanisms in several normal and cancer models. This review provides an overview on the current knowledge about the molecular mechanisms and antitumor activity of these two promising classes of drugs for pancreatic cancer therapy. Finally, the synergistic antiproliferative activity of combined IFN-β and troglitazone treatment on pancreatic cancer cell lines, evaluated in vitro, and the consequent potential clinical applications will be discussed.
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Affiliation(s)
- Alessandra Dicitore
- Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy
| | - Michele Caraglia
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Germano Gaudenzi
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Gloria Manfredi
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Bruno Amato
- Department of Clinical Medicine and Surgery, University "Federico II" of Naples, Italy
| | - Daniela Mari
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Geriatric Unit IRCCS Ca' Grande Foundation Maggiore Policlinico Hospital, Milan, Italy
| | - Luca Persani
- Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Claudio Arra
- Animal Facility, National Cancer Institute of Naples Fondazione "G. Pascale", Naples, Italy
| | - Giovanni Vitale
- Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
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31
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Kearney S, Delgado C, Lenz LL. Differential effects of type I and II interferons on myeloid cells and resistance to intracellular bacterial infections. Immunol Res 2013; 55:187-200. [PMID: 22983898 DOI: 10.1007/s12026-012-8362-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The type I and II interferons (IFNs) play important roles in regulating immune responses during viral and bacterial infections and in the context of autoimmune and neoplastic diseases. These two IFN types bind to distinct cell surface receptors that are expressed by nearly all cells to trigger signal transduction events and elicit diverse cellular responses. In some cases, type I and II IFNs trigger similar cellular responses, while in other cases, the IFNs have unique or antagonistic effects on host cells. Negative regulators of IFN signaling also modulate cellular responses to the IFNs and play important roles in maintaining immunological homeostasis. In this review, we provide an overview of how IFNs stimulate cellular responses. We discuss the disparate effects of type I and II IFNs on host resistance to certain intracellular bacterial infections and provide an overview of models that have been proposed to account for these disparate effects. Mechanisms of antagonistic cross talk between type I and II IFNs are also introduced.
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Affiliation(s)
- Staci Kearney
- Integrated Department of Immunology, University of Colorado School of Medicine, Aurora, CO, USA
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32
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Qu H, Yang L, Meng S, Xu L, Bi Y, Jia X, Li J, Sun L, Liu W. The differential antiviral activities of chicken interferon α (ChIFN-α) and ChIFN-β are related to distinct interferon-stimulated gene expression. PLoS One 2013; 8:e59307. [PMID: 23527158 PMCID: PMC3602166 DOI: 10.1371/journal.pone.0059307] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 02/15/2013] [Indexed: 01/26/2023] Open
Abstract
Chicken interferon α (ChIFN-α) and ChIFN-β are type I IFNs that are important antiviral cytokines in the innate immune system. In the present study, we identified the virus-induced expression of ChIFN-α and ChIFN-β in chicken fibroblast DF-1 cells and systematically evaluated the antiviral activities of recombinant ChIFN-α and ChIFN-β by cytopathic-effect (CPE) inhibition assays. We found that ChIFN-α exhibited stronger antiviral activity than ChIFN-β in terms of inhibiting the replication of vesicular stomatitis virus, Newcastle disease virus and avian influenza virus, respectively. To elucidate the mechanism of differential antiviral activities between the two ChIFNs, we measured the relative mRNA levels of IFN-stimulated genes (ISGs) in IFN-treated DF-1 cells by real-time PCR. ChIFN-α displayed greater induction potency than ChIFN-β on several ISGs encoding antiviral proteins and MHC-I, whereas ChIFN-α was less potent than ChIFN-β for inducing ISGs involved in signaling pathways. In conclusion, ChIFN-α and ChIFN-β presented differential induction potency on various sets of ISGs, and the stronger antiviral activity of ChIFN-α is likely attributed to the greater expression levels of downstream antiviral ISGs.
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Affiliation(s)
- Hongren Qu
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- Graduate University of Chinese Academy of Sciences, Beijing, China
| | - Limin Yang
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Shanshan Meng
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- Graduate University of Chinese Academy of Sciences, Beijing, China
| | - Lei Xu
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- Graduate University of Chinese Academy of Sciences, Beijing, China
| | - Yuhai Bi
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Xiaojuan Jia
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Jing Li
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Lei Sun
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Wenjun Liu
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- Graduate University of Chinese Academy of Sciences, Beijing, China
- China-Japan Joint Laboratory of Molecular Immunology and Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
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33
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Kapil P, Butchi NB, Stohlman SA, Bergmann CC. Oligodendroglia are limited in type I interferon induction and responsiveness in vivo. Glia 2012; 60:1555-66. [PMID: 22736486 PMCID: PMC3422432 DOI: 10.1002/glia.22375] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Accepted: 05/31/2012] [Indexed: 12/13/2022]
Abstract
Type I interferons (IFNα/β) provide a primary defense against infection. Nevertheless, the dynamics of IFNα/β induction and responsiveness by central nervous system (CNS) resident cells in vivo in response to viral infections are poorly understood. Mice were infected with a neurotropic coronavirus with tropism for oligodendroglia and microglia to probe innate antiviral responses during acute encephalomyelitis. Expression of genes associated with the IFNα/β pathways was monitored in microglia and oligodendroglia purified from naïve and infected mice by fluorescent activated cell sorting. Compared with microglia, oligodendroglia were characterized by low basal expression of mRNA encoding viral RNA sensing pattern recognition receptors (PRRs), IFNα/β receptor chains, interferon sensitive genes (ISG), as well as kinases and transcription factors critical in IFNα/β signaling. Although PRRs and ISGs were upregulated by infection in both cell types, the repertoire and absolute mRNA levels were more limited in oligodendroglia. Furthermore, although oligodendroglia harbored higher levels of viral RNA compared with microglia, Ifnα/β was only induced in microglia. Stimulation with the double stranded RNA analogue poly I:C also failed to induce Ifnα/β in oligodendroglia, and resulted in reduced and delayed induction of ISGs compared with microglia. The limited antiviral response by oligodendroglia was associated with a high threshold for upregulation of Ikkε and Irf7 transcripts, both central to amplifying IFNα/β responses. Overall, these data reveal that oligodendroglia from the adult CNS are poor sensors of viral infection and suggest they require exogenous IFNα/β to establish an antiviral state.
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Affiliation(s)
- Parul Kapil
- Department of Neurosciences, NC‐30, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
- Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio
| | - Niranjan B. Butchi
- Department of Neurosciences, NC‐30, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Stephen A. Stohlman
- Department of Neurosciences, NC‐30, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Cornelia C. Bergmann
- Department of Neurosciences, NC‐30, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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Peng F, Wang Y, Sun L, Liu Y, Hu T, Zhang G, Ma G, Su Z. PEGylation of Proteins in Organic Solution: A Case Study for Interferon beta-1b. Bioconjug Chem 2012; 23:1812-20. [PMID: 22873735 DOI: 10.1021/bc300081f] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Fei Peng
- National Key Laboratory of Biochemical
Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
- Graduate University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yinjue Wang
- National Key Laboratory of Biochemical
Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
| | - Lijing Sun
- National Key Laboratory of Biochemical
Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
| | - Yongdong Liu
- National Key Laboratory of Biochemical
Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
| | - Tao Hu
- National Key Laboratory of Biochemical
Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
| | - Guifeng Zhang
- National Key Laboratory of Biochemical
Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
| | - Guanghui Ma
- National Key Laboratory of Biochemical
Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
| | - Zhiguo Su
- National Key Laboratory of Biochemical
Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
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35
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Wang T, Takikawa Y, Sawara K, Yoshida Y, Suzuki K. Negative regulation of human astrocytes by interferon (IFN) α in relation to growth inhibition and impaired glucose utilization. Neurochem Res 2012; 37:1898-905. [PMID: 22627699 DOI: 10.1007/s11064-012-0806-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Revised: 04/13/2012] [Accepted: 05/09/2012] [Indexed: 12/23/2022]
Abstract
The present study assessed the direct effects of IFNs on human astrocytes. Human astrocytes were exposed to human recombinant IFNs, and the proliferation of cells was measured. Type I IFN receptor mRNA and protein expression, the phosphoprotein levels of signaling molecules including JNK, ERK1/2, IκB, p38MAPK, Stat3, and the expression of cytokines were determined respectively. In addition, cellular glucose consumption was measured as well as Glut-1 protein and activation of GSK-3β/mTOR signal were determined. The expression of Type I IFN receptor was detected in cultured human astrocytes. 2 IU/ml IFNα2a and IFNα2b significantly decreased the proliferation of human astrocytes respectively, compared to control. IFNβ had no significant effect on the proliferation of the cells. The phosphorylation of JNK stimulated by all IFNs detected was more pronounced and sustained than ERK1/2 and IκB. No effects were observed on the activation of p38MAPK and Stat3. Moreover, Treatment with IFNα, especially with IFNα2b, decreased glucose consumption and stimulated phosphorylation of GSK-3β and mTOR, but decreased the expression of Glut-1. In contrast, IFNβ had no significant effect on either glucose consumption or activation of GSK-3β/mTOR signals. INFα2b significantly decreased the levels of IL-8 whereas the levels of GM-CSF were increased. The present study demonstrates direct inhibitory effects of IFNα on cell proliferation, cell signaling and glucose utilization in human astrocytes.
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Affiliation(s)
- Ting Wang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, Japan
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Sequence variability of HCV Core region: Important predictors of HCV induced pathogenesis and viral production. INFECTION GENETICS AND EVOLUTION 2011; 11:543-56. [PMID: 21292033 DOI: 10.1016/j.meegid.2011.01.017] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2010] [Revised: 01/17/2011] [Accepted: 01/21/2011] [Indexed: 02/07/2023]
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Kitahara Y, Kawane K, Nagata S. Interferon-induced TRAIL-independent cell death in DNase II-/- embryos. Eur J Immunol 2010; 40:2590-8. [PMID: 20706988 DOI: 10.1002/eji.201040604] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The chromosomal DNA of apoptotic cells and the nuclear DNA expelled from erythroid precursors is cleaved by DNase II in lysosomes after the cells or nuclei are engulfed by macrophages. DNase II(-/-) embryos suffer from lethal anemia due to IFN-beta produced in the macrophages carrying undigested DNA. Here, we show that Type I IFN induced a caspase-dependent cell death in human epithelial cells that were transformed to express a high level of IFN type I receptor. During this death process, a set of genes was strongly activated, one of which encoded TRAIL, a death ligand. A high level of TRAIL mRNA was also found in the fetal liver of the lethally anemic DNase II(-/-) embryos, and a lack of IFN type I receptor in the DNase II(-/-) IFN-IR(-/-) embryos blocked the expression of TRAIL mRNA. However, a null mutation in TRAIL did not rescue the lethal anemia of the DNase II(-/-) embryos, indicating that TRAIL is dispensable for inducing the apoptosis of erythroid cells in DNase II(-/-) embryos, and therefore, that there is a TRAIL-independent mechanism for the IFN-induced apoptosis.
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Affiliation(s)
- Yusuke Kitahara
- Department of Medical Chemistry, Kyoto University Graduate School of Medicine, Yoshida-Konoe, Kyoto, Japan
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38
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Tomita E, Ando K, Sugihara JI, Nishigaki Y, Yamada T, Ando R, Takemura M, Seishima M. Advantage of IFN-beta/alpha2b same-day administration for ribavirin-intolerant patients with chronic hepatitis C. Hepatol Res 2010; 40:261-8. [PMID: 20070395 DOI: 10.1111/j.1872-034x.2009.00602.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Although interferon (IFN)/ribavirin is the mainstream combination treatment for chronic hepatitis C in patients with a high viral load, ribavirin is problematic for women of childbearing age and patients with anemia. Therefore we needed to establish a new regimen without ribavirin. METHODS We devised a new regimen (same-day beta/alpha2b) to administer IFN-beta and alpha2b on the same-day, and compared it with IFN-alpha2b alone and IFN-alpha2b plus ribavirin. The cases were 36 patients (26.1%) in whom ribavirin could not be used (young women, anemia, etc.) among 138 patients who underwent IFN treatment after ribavirin release. RESULTS The percentages of patients withdrawing due to side-effects were 6.8%, 18.8% and 17.0% in the treatment with same-day beta/alpha2b, IFN-alpha2b alone and IFN-alpha2b plus ribavirin groups, respectively. In genotype 1b, the sustained viral response (SVR) was 28.6% (4/14), 13.6% (3/22) and 25.0% (8/32) with a high viral load, and 91.7% (11/12), 27.3% (3/11) and 57.1% (4/7) with a low viral load for the respective groups. According to a study on viral half-life during the early phase of IFN therapy, there was no difference among the regimens of same-day IFN-beta/alpha2b, beta alone, alpha2b alone and twice-daily treatment with IFN-beta. Same-day beta/alpha2b treatment showed a significantly higher SVR rate in moving type patients with a genotype 1b/high viral load. CONCLUSIONS Same-day beta/alpha2b treatment resulted in few cases where therapy was discontinued and showed a high SVR rate. This regimen is especially appropriate in cases where ribavirin has been deemed unsuitable.
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Affiliation(s)
- Eiichi Tomita
- Gastroenterology and Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu City, Gifu 500-8513, Japan
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Miyake K, Imura S, Nishioka M, Batmunkh E, Sugimoto K, Ohmoto Y, Shimada M. Serum evaluation of soluble interferon-alpha/beta receptor and high-sensitivity C-reactive protein for diagnosis of the patients with gastrointestinal and hepatobiliary-pancreatic cancer. Cytokine 2009; 49:251-5. [PMID: 19879773 DOI: 10.1016/j.cyto.2009.09.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2009] [Revised: 09/14/2009] [Accepted: 09/29/2009] [Indexed: 10/20/2022]
Abstract
Serum soluble interferon-alpha/beta receptor (sIFN-alpha/betaR) and high-sensitivity C-reactive protein (hs-CRP) levels were evaluated in the patients with gastrointestinal and hepatobiliary-pancreatic cancer. We compared the sensitivity and specificity of serum sIFN-alpha/betaR with that of serum hs-CRP and evaluated the two diagnostic parameters in combination. Serum sIFN-alpha/betaR levels were measured in 92 patients and 25 healthy individuals by enzyme-linked immunosorbent assay. The diagnoses were 37 cases of hepatocellular carcinoma, 17 cases of pancreatic cancer, 15 cases of colon cancer, 13 cases of biliary tract cancer, and 10 cases of gastric cancer. Serum levels of sIFN-alpha/betaR and hs-CRP were significantly higher in the patients than in healthy individuals (p<0.05). The optimal cut-off values of sIFN-alpha/betaR and hs-CRP were 3600pg/ml and 0.5microg/ml, respectively. The sensitivity and specificity for these thresholds were 94.6% and 88.0%, whereas positive predictive and negative predictive values were 96.7% and 81.5%. These results suggest that a combination of serum sIFN-alpha/betaR and hs-CRP thresholds may be more reliable diagnostic parameter for gastrointestinal and hepatobiliary-pancreatic cancer.
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Affiliation(s)
- Kotaro Miyake
- Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
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40
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Abstract
Type I Interferons (IFN) induce the expression of IFN-stimulated genes (ISG). The products of some of these genes have direct antiviral effects, others are involved in immunoregulation or modulate signaling pathways and gene expression, and others yet are mediators of cell growth and death. Their role in autoimmune diseases has been found to be both beneficial and detrimental.
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Affiliation(s)
- Myriam S Kunzi
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD, USA
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41
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Génin P, Vaccaro A, Civas A. The role of differential expression of human interferon--a genes in antiviral immunity. Cytokine Growth Factor Rev 2009; 20:283-95. [PMID: 19651532 DOI: 10.1016/j.cytogfr.2009.07.005] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Immune recognition of virus-associated molecules by Toll-like receptors (TLRs) and/or RIG-I-like receptors (RLRs) triggers intracellular signaling cascades that converge on the activation of interferon regulatory factors - particularly IRF3 and IRF7, leading to the transcriptional induction of type 1 interferon genes. This review summarizes new data describing how these factors regulate the temporal and quantitative differences in the expression of the multigenic IFN-A family. The distinctive DNA-binding features of IRF3 and IRF7 affect the selectivity and affinity of these factors for IFN-A promoters; modification of the ratio of promoter-bound IRF3 and IRF7 during virus infection may influence both transcriptional activation and repression of IFN-A genes. This review also summarizes the structural differences between IFN-beta and different IFN-alpha subtypes, their interaction with their common receptor IFNAR, and their potency to elicit antiviral, antiproliferative and antitumoral responses. Taken together, this information enhances our understanding of the selective advantage of the multiplicity of IFN-alpha subtypes in the regulation of innate and adaptive immunity.
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Affiliation(s)
- Pierre Génin
- Université Paris Descartes, UPR 2228 - CNRS Laboratoire de Régulation Transcriptionnelle et Maladies Génétiques UFR Biomédicale des Saints-Pères, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France
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42
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Recombinant interferon-beta therapy and neuromuscular disorders. J Neuroimmunol 2009; 212:132-41. [DOI: 10.1016/j.jneuroim.2009.04.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2009] [Revised: 04/21/2009] [Accepted: 04/22/2009] [Indexed: 11/20/2022]
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43
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Vitale G, Caraglia M, van Koetsveld PM, Maroni P, Marra M, Colao A, Lamberts SWJ, Cavagnini F, Hofland LJ. Potential role of type I interferons in the treatment of pituitary adenomas. Rev Endocr Metab Disord 2009; 10:125-33. [PMID: 18604644 DOI: 10.1007/s11154-008-9083-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2008] [Accepted: 06/12/2008] [Indexed: 10/21/2022]
Abstract
Cytokines, particularly those endowed with pro-inflammatory properties, are known to influence the release of anterior pituitary hormones by a direct and indirect action at the level of pituitary gland and hypothalamus. Type I interferons (IFNs) represent a group of cytokines that act through a common receptor composed by two chains (IFNAR-1 and IFNAR-2). Several in vitro and in vivo studies underline the fact that type I IFNs are involved in the regulation of the immune-endocrine circuitry. Treatment with type I IFNs of patients affected by chronic viral hepatitis, multiple sclerosis and tumors influences the secretion of pituitary hormones. This article reviews the current knowledge about the effects of IFN-alpha and IFN-beta on hypothalamic-pituitary function and describes the potential role of type I IFNs in the treatment of pituitary adenomas.
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Affiliation(s)
- Giovanni Vitale
- Istituto Auxologico Italiano IRCCS, University of Milan, Milan, Italy.
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44
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Shiba M, Nonomura N, Nakai Y, Nakayama M, Takayama H, Inoue H, Tsujimura A, Nishimura K, Okuyama A. Type-I interferon receptor expression: its circadian rhythm and downregulation after interferon-alpha administration in peripheral blood cells from renal cancer patients. Int J Urol 2009; 16:356-9. [PMID: 19302507 DOI: 10.1111/j.1442-2042.2009.02265.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To investigate the regulation of interferon-alpha (IFN-alpha) receptor expression in metastatic renal cell carcinoma (RCC) after IFN-alpha administration. METHODS Blood sampling was carried out in eight patients with metastatic RCC and six healthy volunteers. Flow-cytometric analysis using a monoclonal antibody against the active subunit of the type-I IFN-alpha receptor (IFNAR2) was carried out to examine the circadian rhythm of IFNAR2 expression in peripheral blood mononuclear cells (PBMC) as well as its downregulation after IFN-alpha administration. RESULTS According to its circadian rhythm IFNAR2 in PBMC had a peak expression at night. Once IFN-alpha is administered, IFNAR2 levels in PBMC showed downregulation within 48 h and recovered within another 48 h. CONCLUSIONS Our findings might support the establishment of an optimal schedule for IFN-alpha administration.
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Affiliation(s)
- Masahiro Shiba
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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45
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Gerlach N, Gibbert K, Alter C, Nair S, Zelinskyy G, James CM, Dittmer U. Anti-retroviral effects of type I IFN subtypes in vivo. Eur J Immunol 2009; 39:136-46. [PMID: 19130550 DOI: 10.1002/eji.200838311] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Type I IFN play a very important role in immunity against viral infections. Murine type I IFN belongs to a multigene family including 14 IFN-alpha subtypes but the biological functions of IFN-alpha subtypes in retroviral infections are unknown. We have used the Friend retrovirus model to determine the anti-viral effects of IFN-alpha subtypes in vitro and in vivo. IFN-alpha subtypes alpha1, alpha4, alpha6 or alpha9 suppressed Friend virus (FV) replication in vitro, but differed greatly in their anti-viral efficacy in vivo. Treatment of FV-infected mice with the IFN-alpha subtypes alpha1, alpha4 or alpha9, but not alpha6 led to a significant reduction in viral loads. Decreased splenic viral load after IFN-alpha1 treatment correlated with an expansion of activated FV-specific CD8(+) T cells and NK cells into the spleen, whereas in IFN-alpha4- and -alpha9-treated mice it exclusively correlated with the activation of NK cells. The results demonstrate the distinct anti-retroviral effects of different IFN-alpha subtypes, which may be relevant for new therapeutic approaches.
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Affiliation(s)
- Nicole Gerlach
- Institut für Virologie des Universitätsklinikums Essen, Universität Duisburg-Essen, Essen, Germany
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46
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Bukowski RM. What Role Do Combinations of Interferon and Targeted Agents Play in the First-Line Therapy of Metastatic Renal Cell Carcinoma? Clin Genitourin Cancer 2008; 6 Suppl 1:S14-21. [DOI: 10.3816/cgc.2008.s.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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47
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Martinez-Forero I, Pelaez A, Villoslada P. Pharmacogenomics of multiple sclerosis: in search for a personalized therapy. Expert Opin Pharmacother 2008; 9:3053-67. [DOI: 10.1517/14656560802515553] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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48
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Mordstein M, Kochs G, Dumoutier L, Renauld JC, Paludan SR, Klucher K, Staeheli P. Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog 2008; 4:e1000151. [PMID: 18787692 PMCID: PMC2522277 DOI: 10.1371/journal.ppat.1000151] [Citation(s) in RCA: 268] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2008] [Accepted: 08/12/2008] [Indexed: 12/27/2022] Open
Abstract
Virus-infected cells secrete a broad range of interferon (IFN) subtypes which in turn trigger the synthesis of antiviral factors that confer host resistance. IFN-α, IFN-β and other type I IFNs signal through a common universally expressed cell surface receptor, whereas IFN-λ uses a distinct receptor complex for signaling that is not present on all cell types. Since type I IFN receptor-deficient mice (IFNAR10/0) exhibit greatly increased susceptibility to various viral diseases, it remained unclear to which degree IFN-λ might contribute to innate immunity. To address this issue we performed influenza A virus infections of mice which carry functional alleles of the influenza virus resistance gene Mx1 and which, therefore, develop a more complete innate immune response to influenza viruses than standard laboratory mice. We demonstrate that intranasal administration of IFN-λ readily induced the antiviral factor Mx1 in mouse lungs and efficiently protected IFNAR10/0 mice from lethal influenza virus infection. By contrast, intraperitoneal application of IFN-λ failed to induce Mx1 in the liver of IFNAR10/0 mice and did not protect against hepatotropic virus infections. Mice lacking functional IFN-λ receptors were only slightly more susceptible to influenza virus than wild-type mice. However, mice lacking functional receptors for both IFN-α/β and IFN-λ were hypersensitive and even failed to restrict usually non-pathogenic influenza virus mutants lacking the IFN-antagonistic factor NS1. Interestingly, the double-knockout mice were not more susceptible against hepatotropic viruses than IFNAR10/0 mice. From these results we conclude that IFN-λ contributes to inborn resistance against viral pathogens infecting the lung but not the liver. The contribution of IFN-λ to innate immunity against virus-induced diseases has remained unclear to date as appropriate mouse models were not available. We now present evidence that IFN-λ is involved in the antiviral defense. Mice lacking functional IFN-λ receptors were only slightly more susceptible to influenza virus than wild-type mice, but intranasal administration of IFN-λ efficiently protected IFN-α/β receptor-deficient mice from lethal influenza virus infection and induced the antiviral factor Mx1 in lungs. Mice lacking functional receptors for both IFN-α/β and IFN-λ were hypersensitive and failed to restrict even usually non-pathogenic influenza virus mutants lacking the IFN-antagonistic factor NS1. By contrast, intraperitoneal application of IFN-λ failed to induce Mx1 in the liver of mice and did not protect against hepatotropic viruses. Furthermore, double-knockout mice were not more susceptible against hepatotropic viruses than IFN-α/β receptor-deficient mice, indicating that IFN-λ contributes to resistance against viral pathogens infecting the lung but not the liver.
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Affiliation(s)
- Markus Mordstein
- Department of Virology, University of Freiburg, Freiburg, Germany
| | - Georg Kochs
- Department of Virology, University of Freiburg, Freiburg, Germany
| | - Laure Dumoutier
- Ludwig Institute for Cancer Research, University of Louvain, Brussels, Belgium
| | | | - Søren R. Paludan
- Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark
| | - Kevin Klucher
- ZymoGenetics, Inc., Seattle, Washington, United States of America
| | - Peter Staeheli
- Department of Virology, University of Freiburg, Freiburg, Germany
- * E-mail:
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Sottini A, Ghidini C, Serana F, Chiarini M, Valotti M, Badolato R, Radeghieri A, Caimi L, Imberti L. Decreased type I interferon receptor-soluble isoform in antiretroviral-treated HIV-positive children. J Interferon Cytokine Res 2008; 28:181-9. [PMID: 18338950 DOI: 10.1089/jir.2007.0091] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We developed a real-time PCR assay to simultaneously measure the mRNA level of type I interferon (IFN) receptor (IFNAR) components in peripheral blood cells of children with chronic immune stimulation due to HIV infection. All patients were undergoing antiretroviral therapy and were divided into two groups on the basis of the induction of MxA mRNA, a marker of type I IFN bioactivity. We found that IFNAR-2 subunit mRNA was higher than that of the IFNAR-1 subunit, that the mRNA for the IFNAR-2.2 functional isoform was more expressed than that for the truncated IFNAR-2.1 isoform, and both were much more represented than that of the IFNAR-2.3 soluble isoform. We also demonstrated that soluble isoform mRNA was significantly diminished in the subgroup of patients with MxA mRNA below the cutoff value (determined as the 99th percentile of MxA measured in healthy controls). These results suggest that downregulation of the soluble receptor isoform, which would not compete with the functional isoform for binding to the target cytokine, would give type I IFN, eventually induced in these patients in the case of viral reactivation, the opportunity to promptly exert its antiviral activity.
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Affiliation(s)
- Alessandra Sottini
- Laboratorio di Biotecnologie, Department of Diagnostics, Spedali Civili di Brescia, Italy
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50
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Serana F, Sottini A, Ghidini C, Zanotti C, Capra R, Cordioli C, Caimi L, Imberti L. Modulation of IFNAR1 mRNA expression in multiple sclerosis patients. J Neuroimmunol 2008; 197:54-62. [PMID: 18482773 DOI: 10.1016/j.jneuroim.2008.03.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2007] [Revised: 02/29/2008] [Accepted: 03/17/2008] [Indexed: 01/02/2023]
Abstract
Interferon-beta receptor (IFNAR) is composed of 2 subunits, IFNAR1 and IFNAR2, the latter of which is expressed as functional (IFNAR2.2), non-functional (IFNAR2.1) and soluble (IFNAR2.3) isoform. Real-Time PCR analysis of mRNA for all IFNAR components in multiple sclerosis patients naïve for therapy and undergoing long-term treatment with interferon-beta shows that IFNAR1 mRNA level is lower than in healthy controls. If long-term treated patients are divided according to the production of mRNA for Myxovirus protein-A, a marker of interferon-beta bioactivity, IFNAR1 mRNA reaches the values observed in controls only in Myxovirus protein-A-induced patients. Since chronic cell stimulation by interferon-beta induces IFNAR protein down-regulation, we suggest that the increase of IFNAR1 mRNA might serve as a mechanism for counterbalancing the loss of protein receptor, enhancing, at least in this sub-group of patients, cell responsiveness to interferon-beta.
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Affiliation(s)
- Federico Serana
- Laboratorio di Biotecnologie, Diagnostic Department, Spedali Civili di Brescia, p.le Spedali Civili 1, 25123, Brescia, Italy
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