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Qing F, Tian H, Wang B, Xie B, Sui L, Xie X, He W, He T, Li Y, He L, Guo Q, Liu Z. Interferon regulatory factor 7 alleviates the experimental colitis through enhancing IL-28A-mediated intestinal epithelial integrity. J Transl Med 2024; 22:905. [PMID: 39370517 PMCID: PMC11457333 DOI: 10.1186/s12967-024-05673-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 09/02/2024] [Indexed: 10/08/2024] Open
Abstract
BACKGROUND The incidence of inflammatory bowel disease (IBD) is on the rise in developing countries, and investigating the underlying mechanisms of IBD is essential for the development of targeted therapeutic interventions. Interferon regulatory factor 7 (IRF7) is known to exert pro-inflammatory effects in various autoimmune diseases, yet its precise role in the development of colitis remains unclear. METHODS We analyzed the clinical significance of IRF7 in ulcerative colitis (UC) by searching RNA-Seq databases and collecting tissue samples from clinical UC patients. And, we performed dextran sodium sulfate (DSS)-induced colitis modeling using WT and Irf7-/- mice to explore the mechanism of IRF7 action on colitis. RESULTS In this study, we found that IRF7 expression is significantly reduced in patients with UC, and also demonstrated that Irf7-/- mice display heightened susceptibility to DSS-induced colitis, accompanied by elevated levels of colonic and serum pro-inflammatory cytokines, suggesting that IRF7 is able to inhibit colitis. This increased susceptibility is linked to compromised intestinal barrier integrity and impaired expression of key molecules, including Muc2, E-cadherin, β-catenin, Occludin, and Interleukin-28A (IL-28A), a member of type III interferon (IFN-III), but independent of the deficiency of classic type I interferon (IFN-I) and type II interferon (IFN-II). The stimulation of intestinal epithelial cells by recombinant IL-28A augments the expression of Muc2, E-cadherin, β-catenin, and Occludin. The recombinant IL-28A protein in mice counteracts the heightened susceptibility of Irf7-/- mice to colitis induced by DSS, while also elevating the expression of Muc2, E-cadherin, β-catenin, and Occludin, thereby promoting the integrity of the intestinal barrier. CONCLUSION These findings underscore the pivotal role of IRF7 in preserving intestinal homeostasis and forestalling the onset of colitis.
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Affiliation(s)
- Furong Qing
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Hongbo Tian
- Department of Stomatology, Chifeng Maternity Hospital, Chifeng, Inner Mongolia, China
| | - Biyao Wang
- Department of Gastroenterology, The Sixth-Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Biomedical Innovation Center, The Sixth-Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Bingyu Xie
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Lina Sui
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xiaoyan Xie
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Wenji He
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Tiansheng He
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Yumei Li
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Liangmei He
- Department of Gastroenterology, The First-Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Qin Guo
- Department of Gastroenterology, The Sixth-Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
- Biomedical Innovation Center, The Sixth-Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
| | - Zhiping Liu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China.
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China.
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Mesev EV, Lin AE, Guare EG, Heller BL, Douam F, Adamson B, Toettcher JE, Ploss A. Membrane-proximal motifs encode differences in signaling strength between type I and III interferon receptors. Sci Signal 2023; 16:eadf5494. [PMID: 37816090 PMCID: PMC10939449 DOI: 10.1126/scisignal.adf5494] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 09/09/2023] [Indexed: 10/12/2023]
Abstract
Interferons (IFNs) play crucial roles in antiviral defenses. Despite using the same Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) signaling cascade, type I and III IFN receptors differ in the magnitude and dynamics of their signaling in terms of STAT phosphorylation, gene transcription, and antiviral responses. These differences are not due to ligand-binding affinity and receptor abundance. Here, we investigated the ability of the intracellular domains (ICDs) of IFN receptors to differentiate between type I and III IFN signaling. We engineered synthetic, heterodimeric type I and III IFN receptors that were stably expressed at similar amounts in human cells and responded to a common ligand. We found that our synthetic type I IFN receptors stimulated STAT phosphorylation and gene expression to greater extents than did the corresponding type III IFN receptors. Furthermore, we identified short "box motifs" within ICDs that bind to JAK1 that were sufficient to encode differences between the type I and III IFN receptors. Together, our results indicate that specific regions within the ICDs of IFN receptor subunits encode different downstream signaling strengths that enable type I and III IFN receptors to produce distinct signaling outcomes.
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Affiliation(s)
- Emily V. Mesev
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Aaron E. Lin
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Emma G. Guare
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Brigitte L. Heller
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Florian Douam
- Department of Microbiology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA
| | - Britt Adamson
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
- Lewis Sigler Center for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
| | - Jared E. Toettcher
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
- Omenn-Darling Bioengineering Institute, Princeton University, Princeton, NJ 08544, USA
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
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Kang B, Zhang J, Schwoerer MP, Nelson AN, Schoeman E, Guo A, Ploss A, Myhrvold C. Highly multiplexed mRNA quantitation with CRISPR-Cas13. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.16.553527. [PMID: 37645785 PMCID: PMC10461975 DOI: 10.1101/2023.08.16.553527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
RNA quantitation tools are often either high-throughput or cost-effective, but rarely are they both. Existing methods can profile the transcriptome at great expense or are limited to quantifying a handful of genes by labor constraints. A technique that permits more throughput at a reduced cost could enable multi-gene kinetic studies, gene regulatory network analysis, and combinatorial genetic screens. Here, we introduce quantitative Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids (qCARMEN): an RNA quantitation technique which leverages the programmable RNA-targeting capabilities of CRISPR-Cas13 to address this challenge by quantifying over 4,500 gene-sample pairs in a single experiment. Using qCARMEN, we studied the response profiles of interferon-stimulated genes (ISGs) during interferon (IFN) stimulation and flavivirus infection. Additionally, we observed isoform switching kinetics during epithelial-mesenchymal transition. qCARMEN is a simple and inexpensive technique that greatly enhances the scalability of RNA quantitation for novel applications with performance similar to gold-standard methods.
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Affiliation(s)
- Brian Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
| | - Jiayu Zhang
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
| | | | - Amy N. Nelson
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
| | - Emily Schoeman
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
| | - Andrew Guo
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
| | - Cameron Myhrvold
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544
- Omenn-Darling Bioengineering Institute, Princeton University, Princeton, NJ 08544
- Department of Chemistry, Princeton University, Princeton, NJ 08544
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The main protease of SARS-CoV-2 cleaves histone deacetylases and DCP1A, attenuating the immune defense of the interferon-stimulated genes. J Biol Chem 2023; 299:102990. [PMID: 36758802 PMCID: PMC9907797 DOI: 10.1016/j.jbc.2023.102990] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/11/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019, constitutes an emerging human pathogen of zoonotic origin. A critical role in protecting the host against invading pathogens is carried out by interferon-stimulated genes (ISGs), the primary effectors of the type I interferon (IFN) response. All coronaviruses studied thus far have to first overcome the inhibitory effects of the IFN/ISG system before establishing efficient viral replication. However, whether SARS-CoV-2 evades IFN antiviral immunity by manipulating ISG activation remains to be elucidated. Here, we show that the SARS-CoV-2 main protease (Mpro) significantly suppresses the expression and transcription of downstream ISGs driven by IFN-stimulated response elements in a dose-dependent manner, and similar negative regulations were observed in two mammalian epithelial cell lines (simian Vero E6 and human A549). Our analysis shows that to inhibit the ISG production, Mpro cleaves histone deacetylases (HDACs) rather than directly targeting IFN signal transducers. Interestingly, Mpro also abolishes the activity of ISG effector mRNA-decapping enzyme 1a (DCP1A) by cleaving it at residue Q343. In addition, Mpro from different genera of coronaviruses has the protease activity to cleave both HDAC2 and DCP1A, even though the alphacoronaviruse Mpro exhibits weaker catalytic activity in cleaving HDAC2. In conclusion, our findings clearly demonstrate that SARS-CoV-2 Mpro constitutes a critical anti-immune effector that modulates the IFN/ISG system at multiple levels, thus providing a novel molecular explanation for viral immune evasion and allowing for new therapeutic approaches against coronavirus disease 2019 infection.
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Mo Q, Feng K, Dai S, Wu Q, Zhang Z, Ali A, Deng F, Wang H, Ning YJ. Transcriptome profiling highlights regulated biological processes and type III interferon antiviral responses upon Crimean-Congo hemorrhagic fever virus infection. Virol Sin 2023; 38:34-46. [PMID: 36075566 PMCID: PMC10006212 DOI: 10.1016/j.virs.2022.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/12/2022] [Indexed: 11/17/2022] Open
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a biosafety level-4 (BSL-4) pathogen that causes Crimean-Congo hemorrhagic fever (CCHF) characterized by hemorrhagic manifestation, multiple organ failure and high mortality rate, posing great threat to public health. Despite the recently increasing research efforts on CCHFV, host cell responses associated with CCHFV infection remain to be further characterized. Here, to better understand the cellular response to CCHFV infection, we performed a transcriptomic analysis in human kidney HEK293 cells by high-throughput RNA sequencing (RNA-seq) technology. In total, 496 differentially expressed genes (DEGs), including 361 up-regulated and 135 down-regulated genes, were identified in CCHFV-infected cells. These regulated genes were mainly involved in host processes including defense response to virus, response to stress, regulation of viral process, immune response, metabolism, stimulus, apoptosis and protein catabolic process. Therein, a significant up-regulation of type III interferon (IFN) signaling pathway as well as endoplasmic reticulum (ER) stress response was especially remarkable. Subsequently, representative DEGs from these processes were well validated by RT-qPCR, confirming the RNA-seq results and the typical regulation of IFN responses and ER stress by CCHFV. Furthermore, we demonstrate that not only type I but also type III IFNs (even at low dosages) have substantial anti-CCHFV activities. Collectively, the data may provide new and comprehensive insights into the virus-host interactions and particularly highlights the potential role of type III IFNs in restricting CCHFV, which may help inform further mechanistic delineation of the viral infection and development of anti-CCHFV strategies.
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Affiliation(s)
- Qiong Mo
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China; University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Kuan Feng
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Shiyu Dai
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China; University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Qiaoli Wu
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Zhong Zhang
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Ashaq Ali
- University of Chinese Academy of Sciences, Beijing, 101408, China; Centre of Excellence in Science and Applied Technologies, Islamabad, 45320, Pakistan
| | - Fei Deng
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China; Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
| | - Hualin Wang
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China; Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
| | - Yun-Jia Ning
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China; Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
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Affiliation(s)
- Xinjiang Cai
- Department of MedicineUniversity of California, Los Angeles (UCLA)Los AngelesCA
| | - Yin Tintut
- Department of MedicineUniversity of California, Los Angeles (UCLA)Los AngelesCA
- Department of PhysiologyUniversity of CaliforniaLos AngelesCA
- Department of Orthopaedic SurgeryUniversity of CaliforniaLos AngelesCA
- VA Greater Los Angeles Healthcare SystemLos AngelesCA
| | - Linda L. Demer
- Department of MedicineUniversity of California, Los Angeles (UCLA)Los AngelesCA
- Department of BioengineeringUniversity of California, Los Angeles (UCLA)Los AngelesCA
- Department of PhysiologyUniversity of CaliforniaLos AngelesCA
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7
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Signaling Lymphocytic Activation Molecule Family Member 1 Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication. Animals (Basel) 2022; 12:ani12243542. [PMID: 36552462 PMCID: PMC9774311 DOI: 10.3390/ani12243542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/09/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
The porcine reproductive and respiratory syndrome virus (PRRSV) causes a highly contagious disease in domestic swine. Signaling lymphocytic activation molecule family member 1 (SLAMF1) is a costimulatory factor that is involved in innate immunity, inflammation, and infection. Here, we demonstrate that overexpression of the SLAMF1 gene inhibited PRRSV replication significantly and reduced the levels of key signaling pathways, including MyD88, RIG-I, TLR2, TRIF, and inflammatory factors IL-6, IL-1β, IL-8, TNF-β, TNF-α, and IFN-α in vitro. However, the knockdown of the SLAMF1 gene could enhance replication of the PRRSV and the levels of key signaling pathways and inflammatory factors. Overall, our results identify a new, to our knowledge, antagonist of the PRRSV, as well as a novel antagonistic mechanism evolved by inhibiting innate immunity and inflammation, providing a new reference and direction for PRRSV disease resistance breeding.
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Brice AM, Rozario AM, Rawlinson SM, David CT, Wiltzer-Bach L, Jans DA, Ito N, Bell TDM, Moseley GW. Lyssavirus P Protein Isoforms Diverge Significantly in Subcellular Interactions Underlying Mechanisms of Interferon Antagonism. J Virol 2022; 96:e0139622. [PMID: 36222519 PMCID: PMC9599249 DOI: 10.1128/jvi.01396-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 09/09/2022] [Indexed: 11/20/2022] Open
Abstract
Viral hijacking of microtubule (MT)-dependent transport is well understood, but several viruses also express discrete MT-associated proteins (vMAPs), potentially to modulate MT-dependent processes in the host cell. Specific roles for vMAP-MT interactions include subversion of antiviral responses by P3, an isoform of the P protein of rabies virus (RABV; genus Lyssavirus), which mediates MT-dependent antagonism of interferon (IFN)-dependent signal transducers and activators of transcription 1 (STAT1) signaling. P3 also undergoes nucleocytoplasmic trafficking and inhibits STAT1-DNA binding, indicative of intranuclear roles in a multipronged antagonistic strategy. MT association/STAT1 antagonist functions of P3 correlate with pathogenesis, indicating potential as therapeutic targets. However, key questions remain, including whether other P protein isoforms interact with MTs, the relationship of these interactions with pathogenesis, and the extent of conservation of P3-MT interactions between diverse pathogenic lyssaviruses. Using super-resolution microscopy, live-cell imaging, and immune signaling analyses, we find that multiple P protein isoforms associate with MTs and that association correlates with pathogenesis. Furthermore, P3 proteins from different lyssaviruses exhibit variation in intracellular localization phenotypes that are associated with STAT1 antagonist function, whereby P3-MT association is conserved among lyssaviruses of phylogroup I but not phylogroup II, while nucleocytoplasmic localization varies between P3 proteins of the same phylogroup within both phylogroup I and II. Nevertheless, the divergent P3 proteins retain significant IFN antagonist function, indicative of adaptation to favor different inhibitory mechanisms, with MT interaction important to phylogroup I viruses. IMPORTANCE Lyssaviruses, including rabies virus, cause rabies, a progressive encephalomyelitis that is almost invariably fatal. There are no effective antivirals for symptomatic infection, and effective application of current vaccines is limited in areas of endemicity, such that rabies causes ~59,000 deaths per year. Viral subversion of host cell functions, including antiviral immunity, is critical to disease, and isoforms of the lyssavirus P protein are central to the virus-host interface underpinning immune evasion. Here, we show that specific cellular interactions of P protein isoforms involved in immune evasion vary significantly between different lyssaviruses, indicative of distinct strategies to evade immune responses. These findings highlight the diversity of the virus-host interface, an important consideration in the development of pan-lyssavirus therapeutic approaches.
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Affiliation(s)
- Aaron M. Brice
- Viral Pathogenesis Laboratory, Department of Biochemistry and Molecular Biology, Bio21 Institute, The University of Melbourne, Melbourne, Victoria, Australia
- Viral Pathogenesis Laboratory, Department of Microbiology, Monash University, Clayton, Victoria, Australia
| | - Ashley M. Rozario
- School of Chemistry, Monash University, Clayton, Victoria, Australia
| | - Stephen M. Rawlinson
- Viral Pathogenesis Laboratory, Department of Biochemistry and Molecular Biology, Bio21 Institute, The University of Melbourne, Melbourne, Victoria, Australia
- Viral Pathogenesis Laboratory, Department of Microbiology, Monash University, Clayton, Victoria, Australia
| | - Cassandra T. David
- Viral Pathogenesis Laboratory, Department of Biochemistry and Molecular Biology, Bio21 Institute, The University of Melbourne, Melbourne, Victoria, Australia
- Viral Pathogenesis Laboratory, Department of Microbiology, Monash University, Clayton, Victoria, Australia
| | - Linda Wiltzer-Bach
- Viral Pathogenesis Laboratory, Department of Microbiology, Monash University, Clayton, Victoria, Australia
| | - David A. Jans
- Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Naoto Ito
- Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
- United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan
| | - Toby D. M. Bell
- School of Chemistry, Monash University, Clayton, Victoria, Australia
| | - Gregory W. Moseley
- Viral Pathogenesis Laboratory, Department of Biochemistry and Molecular Biology, Bio21 Institute, The University of Melbourne, Melbourne, Victoria, Australia
- Viral Pathogenesis Laboratory, Department of Microbiology, Monash University, Clayton, Victoria, Australia
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Yang Z, Sun B, Xiang J, Wu H, Kan S, Hao M, Chang L, Liu H, Wang D, Liu W. Role of epigenetic modification in interferon treatment of hepatitis B virus infection. Front Immunol 2022; 13:1018053. [PMID: 36325353 PMCID: PMC9618964 DOI: 10.3389/fimmu.2022.1018053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/27/2022] [Indexed: 11/28/2022] Open
Abstract
Human hepatitis B virus (HBV) is a small, enveloped DNA virus that causes acute and chronic hepatitis. Chronic hepatitis B (CHB) is associated with hepatocellular carcinoma pathogenesis. Interferons (IFNs) have been used for the treatment of CHB for a long time, with advantages including less treatment duration and sustained virological response. Presently, various evidence suggests that epigenetic modification of the viral covalently closed circular DNA (cccDNA) and the host genome is crucial for the regulation of viral activity. This modification includes histone acetylation, DNA methylation, N6-methyladenosine, and non-coding RNA modification. IFN treatment for CHB can stimulate multiple IFN-stimulated genes for inhibiting virus replication. IFNs can also affect the HBV life cycle through epigenetic modulation. In this review, we summarized the different mechanisms through which IFN-α inhibits HBV replication, including epigenetic regulation. Moreover, the mechanisms underlying IFN activity are discussed, which indicated its potential as a novel treatment for CHB. It is proposed that epigenetic changes such as histone acetylation, DNA methylation, m6A methylation could be the targets of IFN, which may offer a novel approach to HBV treatment.
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Affiliation(s)
- Zhijing Yang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Baozhen Sun
- Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jingcheng Xiang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Han Wu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Shaoning Kan
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Ming Hao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Lu Chang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Huimin Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
| | - Weiwei Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
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10
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Gibson AR, Sateriale A, Dumaine JE, Engiles JB, Pardy RD, Gullicksrud JA, O’Dea KM, Doench JG, Beiting DP, Hunter CA, Striepen B. A genetic screen identifies a protective type III interferon response to Cryptosporidium that requires TLR3 dependent recognition. PLoS Pathog 2022; 18:e1010003. [PMID: 35584177 PMCID: PMC9154123 DOI: 10.1371/journal.ppat.1010003] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 05/31/2022] [Accepted: 04/11/2022] [Indexed: 11/18/2022] Open
Abstract
Cryptosporidium is a leading cause of severe diarrhea and diarrheal-related death in children worldwide. As an obligate intracellular parasite, Cryptosporidium relies on intestinal epithelial cells to provide a niche for its growth and survival, but little is known about the contributions that the infected cell makes to this relationship. Here we conducted a genome wide CRISPR/Cas9 knockout screen to discover host genes that influence Cryptosporidium parvum infection and/or host cell survival. Gene enrichment analysis indicated that the host interferon response, glycosaminoglycan (GAG) and glycosylphosphatidylinositol (GPI) anchor biosynthesis are important determinants of susceptibility to C. parvum infection and impact on the viability of host cells in the context of parasite infection. Several of these pathways are linked to parasite attachment and invasion and C-type lectins on the surface of the parasite. Evaluation of transcript and protein induction of innate interferons revealed a pronounced type III interferon response to Cryptosporidium in human cells as well as in mice. Treatment of mice with IFNλ reduced infection burden and protected immunocompromised mice from severe outcomes including death, with effects that required STAT1 signaling in the enterocyte. Initiation of this type III interferon response was dependent on sustained intracellular growth and mediated by the pattern recognition receptor TLR3. We conclude that host cell intrinsic recognition of Cryptosporidium results in IFNλ production critical to early protection against this infection.
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Affiliation(s)
- Alexis R. Gibson
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Adam Sateriale
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Jennifer E. Dumaine
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Julie B. Engiles
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Department of Pathobiology, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Ryan D. Pardy
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Jodi A. Gullicksrud
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Keenan M. O’Dea
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - John G. Doench
- Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Daniel P. Beiting
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Christopher A. Hunter
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Boris Striepen
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
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Li SY, Johnson R, Smyth LC, Dragunow M. Platelet-derived growth factor signalling in neurovascular function and disease. Int J Biochem Cell Biol 2022; 145:106187. [PMID: 35217189 DOI: 10.1016/j.biocel.2022.106187] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 02/08/2022] [Accepted: 02/21/2022] [Indexed: 11/25/2022]
Abstract
Platelet-derived growth factors are critical for cerebrovascular development and homeostasis. Abnormalities in this signalling pathway are implicated in neurological diseases, especially those where neurovascular dysfunction and neuroinflammation plays a prominent role in disease pathologies, such as stroke and Alzheimer's disease; the angiogenic nature of this pathway also draws its significance in brain malignancies such as glioblastoma where tumour angiogenesis is profuse. In this review, we provide an updated overview of the actions of the platelet-derived growth factors on neurovascular function, their role in the regulation of perivascular cell types expressing the cognate receptors, neurological diseases associated with aberrance in signalling, and highlight the clinical relevance and therapeutic potentials of this pathway for central nervous system diseases.
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Affiliation(s)
- Susan Ys Li
- Department of Pharmacology and Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
| | - Rebecca Johnson
- Department of Pharmacology and Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
| | - Leon Cd Smyth
- Center for Brain Immunology and Glia, Department of Pathology and Immunology, Washington University in St Louis, MO, USA.
| | - Mike Dragunow
- Department of Pharmacology and Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
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12
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Recipient IL28B genotype CT is a predictor of new onset diabetes mellitus in liver transplant patients with chronic hepatitis C. Int J Diabetes Dev Ctries 2021. [DOI: 10.1007/s13410-021-01015-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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13
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Movaqar A, Yaghoubi A, Rezaee SAR, Jamehdar SA, Soleimanpour S. Coronaviruses construct an interconnection way with ERAD and autophagy. Future Microbiol 2021; 16:1135-1151. [PMID: 34468179 PMCID: PMC8412035 DOI: 10.2217/fmb-2021-0044] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 08/04/2021] [Indexed: 12/20/2022] Open
Abstract
Coronaviruses quickly became a pandemic or epidemic, affecting large numbers of humans, due to their structural features and also because of their impacts on intracellular communications. The knowledge of the intracellular mechanism of virus distribution could help understand the coronavirus's proper effects on different pathways that lead to the infections. They protect themselves from recognition and damage the infected cell by using an enclosed membrane through hijacking the autophagy and endoplasmic reticulum-associated protein degradation pathways. The present study is a comprehensive review of the coronavirus strategy in upregulating the communication network of autophagy and endoplasmic reticulum-associated protein degradation.
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Affiliation(s)
- Aref Movaqar
- Antimicrobial Resistance Research Center, Mashhad University of Medical Science, Mashhad, Iran
- Department of Microbiology & Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Atieh Yaghoubi
- Antimicrobial Resistance Research Center, Mashhad University of Medical Science, Mashhad, Iran
- Department of Microbiology & Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - SA Rahim Rezaee
- Inflammation & Inflammatory Diseases Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saeid A Jamehdar
- Antimicrobial Resistance Research Center, Mashhad University of Medical Science, Mashhad, Iran
- Department of Microbiology & Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saman Soleimanpour
- Antimicrobial Resistance Research Center, Mashhad University of Medical Science, Mashhad, Iran
- Department of Microbiology & Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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14
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IL29 expression in gingival tissues of chronic periodontitis and aggressive periodontitis patients: An immunohistochemical analysis. Dent Res J (Isfahan) 2021; 18:66. [PMID: 34584644 PMCID: PMC8428285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 04/03/2020] [Accepted: 09/20/2020] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Interleukin-29 (IL-29) is one of the cytokines which has immunomodulatory properties and might play a role in the pathogenesis of periodontal diseases. The aim of this study was an immunohistochemical analysis of IL-29 in gingival tissues of chronic and aggressive periodontitis. MATERIALS AND METHODS In this cross-sectional study based on clinical evaluation and inclusion and exclusion criteria, 20 patients with generalized chronic periodontitis, 13 patients with generalized aggressive periodontitis, and 20 periodontally healthy individuals were enrolled. Gingival tissue samples were obtained during periodontal flap and crown lengthening surgery in periodontal patients and healthy individuals, respectively. Tissue samples were examined to determine the level of IL-29 expression by immunohistochemistry. The data were analyzed using SPSS and paired t-test, ANOVA test, and Tukey's test (P < 0.05). RESULTS A total of 53 participants (34 females and 19 males) were enrolled in this study. IL-29 expression in the connective tissue of the patient groups was more than the healthy one (P < 0.001). In the aggressive periodontitis group, there was a significant increase of IL-29 expression compared to the other two groups, but there was no significant difference between the chronic periodontitis and healthy groups. CONCLUSION According to the results of this study, IL-29 expression was increased in the gingival tissue of aggressive and chronic periodontitis. IL-29 local expression in aggressive periodontitis is higher than the chronic periodontitis and healthy groups, which could suggest the role of IL-29 in the etiopathogenesis of aggressive periodontitis.
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15
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McElrath C, Espinosa V, Lin JD, Peng J, Sridhar R, Dutta O, Tseng HC, Smirnov SV, Risman H, Sandoval MJ, Davra V, Chang YJ, Pollack BP, Birge RB, Galan M, Rivera A, Durbin JE, Kotenko SV. Critical role of interferons in gastrointestinal injury repair. Nat Commun 2021; 12:2624. [PMID: 33976143 PMCID: PMC8113246 DOI: 10.1038/s41467-021-22928-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 04/06/2021] [Indexed: 12/13/2022] Open
Abstract
The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.
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Affiliation(s)
- Constance McElrath
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Vanessa Espinosa
- Pediatrics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Jian-Da Lin
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Jianya Peng
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Department of Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Raghavendra Sridhar
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Orchi Dutta
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Pediatrics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Hsiang-Chi Tseng
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Sergey V Smirnov
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Heidi Risman
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Marvin J Sandoval
- Department of Pathology, New York University School of Medicine, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA
| | - Viralkumar Davra
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Yun-Juan Chang
- Office of Advance Research Computing, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Brian P Pollack
- Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA
- Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Raymond B Birge
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Center for Cell Signaling, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Mark Galan
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Amariliz Rivera
- Pediatrics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Joan E Durbin
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Sergei V Kotenko
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA.
- Center for Cell Signaling, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA.
- Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, Newark, NJ, USA.
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA.
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16
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Goh ZY, Ren EC, Ko HL. Intracellular interferon signalling pathways as potential regulators of covalently closed circular DNA in the treatment of chronic hepatitis B. World J Gastroenterol 2021; 27:1369-1391. [PMID: 33911462 PMCID: PMC8047536 DOI: 10.3748/wjg.v27.i14.1369] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/23/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Infection with the hepatitis B virus (HBV) is still a major global health threat as 250 million people worldwide continue to be chronically infected with the virus. While patients may be treated with nucleoside/nucleotide analogues, this only suppresses HBV titre to sub-detection levels without eliminating the persistent HBV covalently closed circular DNA (cccDNA) genome. As a result, HBV infection cannot be cured, and the virus reactivates when conditions are favorable. Interferons (IFNs) are cytokines known to induce powerful antiviral mechanisms that clear viruses from infected cells. They have been shown to induce cccDNA clearance, but their use in the treatment of HBV infection is limited as HBV-targeting immune cells are exhausted and HBV has evolved multiple mechanisms to evade and suppress IFN signalling. Thus, to fully utilize IFN-mediated intracellular mechanisms to effectively eliminate HBV, instead of direct IFN administration, novel strategies to sustain IFN-mediated anti-cccDNA and antiviral mechanisms need to be developed. This review will consolidate what is known about how IFNs act to achieve its intracellular antiviral effects and highlight the critical interferon-stimulated gene targets and effector mechanisms with potent anti-cccDNA functions. These include cccDNA degradation by APOBECs and cccDNA silencing and transcription repression by epigenetic modifications. In addition, the mechanisms that HBV employs to disrupt IFN signalling will be discussed. Drugs that have been developed or are in the pipeline for components of the IFN signalling pathway and HBV targets that detract IFN signalling mechanisms will also be identified and discussed for utility in the treatment of HBV infections. Together, these will provide useful insights into design strategies that specifically target cccDNA for the eradication of HBV.
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Affiliation(s)
- Zhi Yi Goh
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore 119077, Singapore
| | - Ee Chee Ren
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore
| | - Hui Ling Ko
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
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Read SA, Gloss BS, Liddle C, George J, Ahlenstiel G. Interferon-λ3 Exacerbates the Inflammatory Response to Microbial Ligands: Implications for SARS-CoV-2 Pathogenesis. J Inflamm Res 2021; 14:1257-1270. [PMID: 33833547 PMCID: PMC8021260 DOI: 10.2147/jir.s301476] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 02/23/2021] [Indexed: 12/13/2022] Open
Abstract
Introduction Interferon lambdas (IFN-λs) are antiviral cytokines that restrict pathogen infection and dissemination at barrier surfaces. Controlled expression of IFN-λs efficiently eliminates acute infections by activating a suite of interferon stimulated genes that inhibit viral propagation and activate local immune cells. Excessive or prolonged production of IFN-λs can however mediate tissue inflammation and disrupt epithelial barriers in both viral and non-viral disease. The mechanism by which IFN-λs drive this disease pathogenesis is poorly understood but may be caused by IFN-λ-mediated amplification of other innate immune signaling pathways. Methods Monocyte-derived macrophages were differentiated ± IFN-λ3 and treated with KDO-lipid A, poly I:C or zymosan, representing bacterial, viral or fungal ligands, respectively. Transcriptome and protein expression were quantified by RNA sequencing/PCR and ELISA/bead array, respectively. Bioinformatic analysis was used to define transcription factor profiles and signaling pathways amplified by IFN-λ3. Finally, the SARS-CoV-2 dataset GSE152075 was queried to compare the effects of IFNL versus IFNA expression in relation to viral load and nasopharyngeal transcriptomes. Results IFN-λ3 exacerbated inflammatory and chemotactic responses unique to each microbial ligand, as measured by RNA sequencing and by ELISA/bead array. Functional annotation identified pathways amplified by IFN-λ3, including inflammasome activation. Inflammasome amplification was confirmed in vitro, as measured by caspase 1 activity and IL-1β cleavage. Lastly, SARS-CoV-2 infected nasopharyngeal transcriptomes expressing IFN-λs but not IFN-αs were implicated in myeloid cell-driven pathogenesis including neutrophil degranulation, complement and coagulation cascades. Discussion These data suggest that IFN-λs contribute to disease pathology by exacerbating innate immune responses during chronic or severe disease states. IFN-λs may contribute to SARS-CoV-2 disease severity, however further study is required to confirm true causation.
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Affiliation(s)
- Scott A Read
- Blacktown Clinical School, Western Sydney University, Blacktown, NSW, 2148, Australia.,Blacktown Hospital, WSLHD, Blacktown, NSW, 2148, Australia.,Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Brian S Gloss
- Westmead Research Hub, Westmead Institute for Medical Research, Westmead, NSW, 2145, Australia
| | - Christopher Liddle
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Golo Ahlenstiel
- Blacktown Clinical School, Western Sydney University, Blacktown, NSW, 2148, Australia.,Blacktown Hospital, WSLHD, Blacktown, NSW, 2148, Australia.,Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
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18
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Fu Z, Yang R, Yu G, Ma Z. Tissue comparison of transcriptional response to acute acidification stress of barramundi Lates calcarifer in coastal and estuarine areas. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS 2021; 38:100830. [PMID: 33812155 DOI: 10.1016/j.cbd.2021.100830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 03/19/2021] [Accepted: 03/21/2021] [Indexed: 10/21/2022]
Abstract
In order to explore the common and unique physiological changes in tissues of juvenile barramundi Lates calcarifer in acidified water environment, RNA sequence analysis was used to analyze the molecular responses of liver, head kidney, and gill of juvenile barramundi in pH 7.4 and pH 8.1 seawater environment. The number of differential expression genes identified in liver, head kidney and gill were 860, 388 and 1792, respectively. Through functional enrichment analysis, the differential expression genes common to the three tissues were all related to immunity. Among the unique differential genes in the liver, pathways related to digestion, endocrine, and metabolism were enriched. Among the unique differential expression genes in gill, pathways related to genetic information processing, immunity and metabolism were enriched. The findings of the present study uncover the transcriptional changes in fish correspond to environmental pH change, and provide a better understanding on the biological process at molecular level to environmental pH adapting. This work highlights that assessments for the potential of estuarine fishes to cope with environmental pH change to develop the future conservation strategies.
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Affiliation(s)
- Zhengyi Fu
- Tropical Aquaculture Research and Development Center, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Sanya 572018, PR China; Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs, Guangzhou 510300, PR China; Sanya Tropical Fisheries Research Institute, Sanya 572018, PR China
| | - Rui Yang
- Tropical Aquaculture Research and Development Center, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Sanya 572018, PR China; Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs, Guangzhou 510300, PR China; Sanya Tropical Fisheries Research Institute, Sanya 572018, PR China
| | - Gang Yu
- Tropical Aquaculture Research and Development Center, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Sanya 572018, PR China; Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs, Guangzhou 510300, PR China; Sanya Tropical Fisheries Research Institute, Sanya 572018, PR China
| | - Zhenhua Ma
- Tropical Aquaculture Research and Development Center, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Sanya 572018, PR China; Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs, Guangzhou 510300, PR China; Sanya Tropical Fisheries Research Institute, Sanya 572018, PR China.
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19
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Wu X, Zhao Y, Gu Y, Li K, Wang X, Zhang J. Interferon-Lambda 1 Inhibits Staphylococcus aureus Colonization in Human Primary Keratinocytes. Front Pharmacol 2021; 12:652302. [PMID: 33828484 PMCID: PMC8019897 DOI: 10.3389/fphar.2021.652302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/10/2021] [Indexed: 11/13/2022] Open
Abstract
Atopic dermatitis (AD) is a common inflammatory skin disease. Staphylococcus aureus (S. aureus) colonization in skin lesions occurs in approximately 70% of AD patients. It has been found that IFN-λ1 can inhibit the colonization of S. aureus in normal human nasal mucosa. IFN-λ1 can increase IL-28RA in infected human keratinocytes. In this study, we found that IFN-λ1 can increase mRNA expression of FLG and antimicrobial peptides (AMPs) and inhibit TSLP mRNA expression in infected human keratinocytes. IFN-λ1 can increase intracellular ROS level, decrease STAT1 phosphorylation, and inhibit the colonization of S. aureus in human primary keratinocytes. These effects were attenuated by knocking-down IL-28R and NADPH oxidase inhibitor, suggesting that this function was mediated by JAK-STAT1 signaling pathway. These results suggest that IFN-λ1 might have an inhibitory effect on S. aureus colonization in AD lesions. Our findings might have potential value in the treatment for AD.
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Affiliation(s)
- Xia Wu
- Department of Dermatology, Peking University People's Hospital, Beijing, China
| | - Yan Zhao
- Department of Dermatology, Peking University People's Hospital, Beijing, China
| | - Ying Gu
- Department of Dermatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Kun Li
- Department of Dermatology, Peking University People's Hospital, Beijing, China
| | - Xiaojie Wang
- Department of Dermatology, Peking University People's Hospital, Beijing, China
| | - Jianzhong Zhang
- Department of Dermatology, Peking University People's Hospital, Beijing, China
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20
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Keshani F, Tabari Z, Hematzadeh S. IL29 expression in gingival tissues of chronic periodontitis and aggressive periodontitis patients: An immunohistochemical analysis. Dent Res J (Isfahan) 2021. [DOI: 10.4103/1735-3327.324025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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21
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Ely A, Singh P, Smith TS, Arbuthnot P. In vitro transcribed mRNA for expression of designer nucleases: Advantages as a novel therapeutic for the management of chronic HBV infection. Adv Drug Deliv Rev 2021; 168:134-146. [PMID: 32485207 DOI: 10.1016/j.addr.2020.05.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 05/14/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023]
Abstract
Chronic infection with the hepatitis B virus (HBV) remains a significant worldwide medical problem. While diseases caused by HIV infection, tuberculosis and malaria are on the decline, new cases of chronic hepatitis B are on the rise. Because often fatal complications of cirrhosis and hepatocellular carcinoma are associated with chronic hepatitis B, the need for a cure is as urgent as ever. Currently licensed therapeutics fail to eradicate the virus and this is attributable to persistence of the viral replication intermediate comprising covalently closed circular DNA (cccDNA). Elimination or inactivation of the viral cccDNA is thus a goal of research aimed at hepatitis B cure. The ability to engineer nucleases that are capable of specific cleavage of a DNA sequence now provides the means to disable cccDNA permanently. The scientific literature is replete with many examples of using designer zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and RNA-guided endonucleases (RGENs) to inactivate HBV. However, important concerns about safety, dose control and efficient delivery need to be addressed before the technology is employed in a clinical setting. Use of in vitro transcribed mRNA to express therapeutic gene editors goes some way to overcoming these concerns. The labile nature of RNA limits off-target effects and enables dose control. Compatibility with hepatotropic non-viral vectors is convenient for the large scale preparation that will be required for advancing gene editing as a mode of curing chronic hepatitis B.
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22
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Qin M, Chen W, Li Z, Wang L, Ma L, Geng J, Zhang Y, Zhao J, Zeng Y. Role of IFNLR1 gene in PRRSV infection of PAM cells. J Vet Sci 2021; 22:e39. [PMID: 34056880 PMCID: PMC8170216 DOI: 10.4142/jvs.2021.22.e39] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/11/2021] [Accepted: 04/15/2021] [Indexed: 01/01/2023] Open
Abstract
Background Interferon lambda receptor 1 (IFNLR1) is a type II cytokine receptor that clings to interleukins IL-28A, IL29B, and IL-29 referred to as type III IFNs (IFN-λs). IFN-λs act through the JAK-STAT signaling pathway to exert antiviral effects related to preventing and curing an infection. Although the immune function of IFN-λs in virus invasion has been described, the molecular mechanism of IFNLR1 in that process is unclear. Objectives The purpose of this study was to elucidate the role of IFNLR1 in the pathogenesis and treatment of porcine reproductive and respiratory syndrome virus (PRRSV). Methods The effects of IFNLR1 on the proliferation of porcine alveolar macrophages (PAMs) during PRRSV infection were investigated using interference and overexpression methods. Results In this study, the expressions of the IFNLR1 gene in the liver, large intestine, small intestine, kidney, and lung tissues of Dapulian pigs were significantly higher than those in Landrace pigs. It was determined that porcine IFNLR1 overexpression suppresses PRRSV replication. The qRT-PCR results revealed that overexpression of IFNLR1 upregulated antiviral and IFN-stimulated genes. IFNLR1 overexpression inhibits the proliferation of PAMs and upregulation of p-STAT1. By contrast, knockdown of IFNLR1 expression promotes PAMs proliferation. The G0/G1 phase proportion in IFNLR1-overexpressing cells increased, and the opposite change was observed in IFNLR1-underexpressing cells. After inhibition of the JAK/STAT signaling pathway, the G2/M phase proportion in the IFNLR1-overexpressing cells showed a significant increasing trend. In conclusion, overexpression of IFNLR1 induces activation of the JAK/STAT pathway, thereby inhibiting the proliferation of PAMs infected with PRRSV. Conclusion Expression of the IFNLR1 gene has an important regulatory role in PRRSV-infected PAMs, indicating it has potential as a molecular target in developing a new strategy for the treatment of PRRSV.
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Affiliation(s)
- Ming Qin
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai' an City, Shandong Province 271018, China
| | - Wei Chen
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai' an City, Shandong Province 271018, China
| | - Zhixin Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai' an City, Shandong Province 271018, China
| | - Lixue Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai' an City, Shandong Province 271018, China
| | - Lixia Ma
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai' an City, Shandong Province 271018, China
| | - Jinhong Geng
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai' an City, Shandong Province 271018, China
| | - Yu Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai' an City, Shandong Province 271018, China
| | - Jing Zhao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai' an City, Shandong Province 271018, China
| | - Yongqing Zeng
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai' an City, Shandong Province 271018, China.
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Ahn D, Prince A. Participation of the IL-10RB Related Cytokines, IL-22 and IFN-λ in Defense of the Airway Mucosal Barrier. Front Cell Infect Microbiol 2020; 10:300. [PMID: 32637365 PMCID: PMC7318800 DOI: 10.3389/fcimb.2020.00300] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 05/19/2020] [Indexed: 12/12/2022] Open
Abstract
The airway epithelial barrier is a major barrier protecting against clinically significant infections of the lung. Its integrity is often compromised due to mechanical, chemical, or infectious causes. Opportunistic bacterial pathogens are poised to cause parenchymal infection and become difficult to eradicate due to adaptive metabolic changes, biofilm formation, and the acquisition of antimicrobial resistance and fitness genes. Enhancing mucosal defenses by modulating the cytokines that regulate barrier functions, such as interleukin-22 (IL-22) and interferon-λ (IFN-λ), members of the IL-10 family of cytokines, is an attractive approach to prevent these infections that are associated with high morbidity and mortality. These cytokines both signal through the cognate receptor IL-10RB, have related protein structures and common downstream signaling suggesting shared roles in host respiratory defense. They are typically co-expressed in multiple models of infections, but with differing kinetics. IL-22 has an important role in the producing antimicrobial peptides, upregulating expression of junctional proteins in the airway epithelium and working in concert with other inflammatory cytokines such as IL-17. Conversely, IFN-λ, a potent antiviral in influenza infection with pro-inflammatory properties, appears to decrease junctional integrity allowing for bacterial and immune cell translocation. The effects of these cytokines are pleotropic, with pathogen and tissue specific consequences. Understanding how these cytokines work in the mucosal defenses of the respiratory system may suggest potential targets to prevent invasive infections of the damaged lung.
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Affiliation(s)
| | - Alice Prince
- Department of Pediatrics, Columbia University Medical Center, New York, NY, United States
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24
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Vlachiotis S, Andreakos E. Lambda interferons in immunity and autoimmunity. J Autoimmun 2019; 104:102319. [DOI: 10.1016/j.jaut.2019.102319] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 08/09/2019] [Indexed: 01/23/2023]
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25
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Ghosh S, Padmanabhan A, Vaidya T, Watson AM, Bhutto IA, Hose S, Shang P, Stepicheva N, Yazdankhah M, Weiss J, Das M, Gopikrishna S, Aishwarya, Yadav N, Berger T, Mak TW, Xia S, Qian J, Lutty GA, Jayagopal A, Zigler JS, Sethu S, Handa JT, Watkins SC, Ghosh A, Sinha D. Neutrophils homing into the retina trigger pathology in early age-related macular degeneration. Commun Biol 2019; 2:348. [PMID: 31552301 PMCID: PMC6754381 DOI: 10.1038/s42003-019-0588-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 08/27/2019] [Indexed: 12/12/2022] Open
Abstract
Age-related macular degeneration (AMD) is an expanding problem as longevity increases worldwide. While inflammation clearly contributes to vision loss in AMD, the mechanism remains controversial. Here we show that neutrophils are important in this inflammatory process. In the retinas of both early AMD patients and in a mouse model with an early AMD-like phenotype, we show neutrophil infiltration. Such infiltration was confirmed experimentally using ribbon-scanning confocal microscopy (RSCM) and IFNλ- activated dye labeled normal neutrophils. With neutrophils lacking lipocalin-2 (LCN-2), infiltration was greatly reduced. Further, increased levels of IFNλ in early AMD trigger neutrophil activation and LCN-2 upregulation. LCN-2 promotes inflammation by modulating integrin β1 levels to stimulate adhesion and transmigration of activated neutrophils into the retina. We show that in the mouse model, inhibiting AKT2 neutralizes IFNλ inflammatory signals, reduces LCN-2-mediated neutrophil infiltration, and reverses early AMD-like phenotype changes. Thus, AKT2 inhibitors may have therapeutic potential in early, dry AMD.
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Affiliation(s)
- Sayan Ghosh
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | | | | | - Alan M. Watson
- Center for Biologic Imaging and Department of Cellular Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Imran A. Bhutto
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Stacey Hose
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Peng Shang
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Nadezda Stepicheva
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Meysam Yazdankhah
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Joseph Weiss
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | | | | | - Aishwarya
- Narayana Nethralaya Foundation, Bengaluru, India
| | - Naresh Yadav
- Narayana Nethralaya Foundation, Bengaluru, India
| | - Thorsten Berger
- The Campbell Family Institute for Breast Cancer Research and Ontario Cancer Institute, University Health Network, Toronto, ON Canada
| | - Tak W. Mak
- The Campbell Family Institute for Breast Cancer Research and Ontario Cancer Institute, University Health Network, Toronto, ON Canada
| | - Shuli Xia
- Hugo W. Moser Research Institute at Kennedy Krieger, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Jiang Qian
- The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Gerard A. Lutty
- The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Ashwath Jayagopal
- Pharma Research and Early Development, Roche Innovation Center, F. Hoffmann-La Roche, Ltd, Basel, Switzerland
- Present Address: Kodiak Sciences, Palo Alto, CA USA
| | - J. Samuel Zigler
- The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD USA
| | | | - James T. Handa
- The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Simon C. Watkins
- Center for Biologic Imaging and Department of Cellular Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | | | - Debasish Sinha
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
- The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD USA
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26
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Zhang AM, Wang Y, Xia X, Song Y. Genetic Polymorphisms of the IFNLR1 Gene Correlate with HCV Infection and Biochemical Features of Chronic HCV Patients in Yunnan, China. Immunol Invest 2019; 49:453-461. [PMID: 31366248 DOI: 10.1080/08820139.2019.1642914] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) infection could lead to serious liver diseases, but the pathogenic mechanisms were not completely clear. Cytokines play critical roles in infection, and the genetic polymorphisms in the cytokine genes are widely studied in infectious diseases. The variations in the IL28B gene were associated with HCV infection, viral clearance, and biochemical features of patients, but the studies of its receptor (IFNLR1/IL10RB) were rare. In this study, we collected 395 chronic HCV patients and 397 normal controls to investigate the genetic role of the IFNLR1 gene. Eight tagSNPs were genotyped, and the haplotypes were constructed. Genotypes CT (23.80% vs. 17.13%) and TT (75.19% vs. 81.36%) of rs7532146 showed higher and lower frequencies in HCV patients than that in controls (P = .022; P = .039). Haplotypes GGAATCTC (P = .028) and AAAGCCCT (P = .002) were risk factors for HCV infection, but haplotype GAAATCTT (P = .027) played protective role in HCV infection. Moreover, we identified that the ALT level was significantly lower in HCV patients with genotype TT of rs4489498 than those with other genotypes (CC vs. TT: P = .037; CT vs. TT: P = .013). HCV viral load was highest in HCV patients with genotype CC of rs4489498 than in patients with other two genotypes (CC vs. CT: P = .006; CC vs. TT: P = .039). In conclusion, the genotypes and haplotypes in the IFNLR1 gene were associated with HCV infection and biochemical features of Chinese HCV patients.
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Affiliation(s)
- A-Mei Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yiqian Wang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Xueshan Xia
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yuzhu Song
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
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Yin X, Zhang S, Li B, Zhang Y, Zhang X. IL28RA inhibits human epidermal keratinocyte proliferation by inhibiting cell cycle progression. Mol Biol Rep 2019; 46:1189-1197. [PMID: 30632069 DOI: 10.1007/s11033-019-04586-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 01/02/2019] [Indexed: 02/08/2023]
Abstract
Interleukin (IL) 28 receptor α (IL28RA) is a well-known candidate for psoriasis susceptibility based on previous genome-wide association study (GWAS) analysis. However, the function of IL28RA in psoriasis has not been elucidated. In the present study, the expression of IL28RA was significantly decreased in lesional tissues from patients with plaque psoriasis when compared with the expression observed in adjacent non-lesional tissues. In vitro studies further demonstrated that in the presence of IL-29, HaCaT keratinocytes with IL28RA knockdown exhibited a faster rate of proliferation than control cells, and an enhanced ratio of cells in the S and G2/M phase. By contrast, IL28RA overexpression inhibited the proliferation of HaCaT keratinocytes and caused cell cycle arrest at the G0/G1 phases. Western blot analysis revealed that knockdown of IL28RA upregulated cyclinB1 expression and downregulated cyclinE expression; the opposite results were observed in the IL28RA-overexpressing HaCaT cells. Finally, a mechanistic study revealed that IL28RA functions through the activation of the Janus kinase-signal transducer and activator of transcription signaling pathway to exert its anti-proliferative effect. These results suggested that weak expression of IL28RA may contribute to the pathogenesis of psoriasis and that IL28RA may be an effective drug target for the treatment of psoriasis. However, further in vivo studies are required.
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Affiliation(s)
- Xueli Yin
- Institute of Dermatology and Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui, China
- Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Shengquan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Bao Li
- Institute of Dermatology and Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui, China
- Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Yaohua Zhang
- Institute of Dermatology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Jing'an District, Shanghai, 200040, China.
| | - Xuejun Zhang
- Institute of Dermatology and Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui, China.
- Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, 230032, China.
- Institute of Dermatology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Jing'an District, Shanghai, 200040, China.
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An information-theoretic framework for deciphering pleiotropic and noisy biochemical signaling. Nat Commun 2018; 9:4591. [PMID: 30389942 PMCID: PMC6214929 DOI: 10.1038/s41467-018-07085-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 10/12/2018] [Indexed: 12/24/2022] Open
Abstract
Many components of signaling pathways are functionally pleiotropic, and signaling responses are marked with substantial cell-to-cell heterogeneity. Therefore, biochemical descriptions of signaling require quantitative support to explain how complex stimuli (inputs) are encoded in distinct activities of pathways effectors (outputs). A unique perspective of information theory cannot be fully utilized due to lack of modeling tools that account for the complexity of biochemical signaling, specifically for multiple inputs and outputs. Here, we develop a modeling framework of information theory that allows for efficient analysis of models with multiple inputs and outputs; accounts for temporal dynamics of signaling; enables analysis of how signals flow through shared network components; and is not restricted by limited variability of responses. The framework allows us to explain how identity and quantity of type I and type III interferon variants could be recognized by cells despite activating the same signaling effectors.
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29
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Andreakos E, Salagianni M, Galani IE, Koltsida O. Interferon-λs: Front-Line Guardians of Immunity and Homeostasis in the Respiratory Tract. Front Immunol 2017; 8:1232. [PMID: 29033947 PMCID: PMC5626824 DOI: 10.3389/fimmu.2017.01232] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 09/19/2017] [Indexed: 12/18/2022] Open
Abstract
Type III interferons (IFNs), also termed lambda IFNs (IFNλs) or interleukins-28/29, constitute a new addition to the IFN family. They are induced upon infection and are particularly abundant at barrier surfaces, such as the respiratory and gastrointestinal tracts. Although they signal through a unique heterodimeric receptor complex comprising IFNLR1 and IL10RB, they activate a downstream signaling pathway remarkably similar to that of type I IFNs and share many functions with them. Yet, they also have important differences which are only now starting to unfold. Here, we review the current literature implicating type III IFNs in the regulation of immunity and homeostasis in the respiratory tract. We survey the common and unique characteristics of type III IFNs in terms of expression patterns, cellular targets, and biological activities and discuss their emerging role in first line defenses against respiratory viral infections. We further explore their immune modulatory functions and their involvement in the regulation of inflammatory responses during chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Type III IFNs are, therefore, arising as front-line guardians of immune defenses in the respiratory tract, fine tuning inflammation, and as potential novel therapeutics for the treatment of diverse respiratory diseases, including influenza virus infection and asthma.
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Affiliation(s)
- Evangelos Andreakos
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Maria Salagianni
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Ioanna E Galani
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Ourania Koltsida
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
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30
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Chiriac MT, Buchen B, Wandersee A, Hundorfean G, Günther C, Bourjau Y, Doyle SE, Frey B, Ekici AB, Büttner C, Weigmann B, Atreya R, Wirtz S, Becker C, Siebler J, Neurath MF. Activation of Epithelial Signal Transducer and Activator of Transcription 1 by Interleukin 28 Controls Mucosal Healing in Mice With Colitis and Is Increased in Mucosa of Patients With Inflammatory Bowel Disease. Gastroenterology 2017; 153:123-138.e8. [PMID: 28342759 DOI: 10.1053/j.gastro.2017.03.015] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 03/09/2017] [Accepted: 03/10/2017] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS We investigated the roles of interleukin 28A (also called IL28A or interferon λ2) in intestinal epithelial cell (IEC) activation, studying its effects in mouse models of inflammatory bowel diseases (IBD) and intestinal mucosal healing. METHODS Colitis was induced in C57BL/6JCrl mice (controls), mice with IEC-specific disruption of Stat1 (Stat1IEC-KO), mice with disruption of the interferon λ receptor 1 gene (Il28ra-/-), and mice with disruption of the interferon regulatory factor 3 gene (Irf3-/-), with or without disruption of Irf7 (Irf7-/-). We used high-resolution mini-endoscopy and in vivo imaging methods to assess colitis progression. We used 3-dimensional small intestine and colon organoids, along with RNA-Seq and gene ontology methods, to characterize the effects of IL28 on primary IECs. We studied the effects of IL28 on the human intestinal cancer cell line Caco-2 in a wound-healing assay, and in mice colon wounds. Colonic biopsies and resected tissue from patients with IBD (n = 62) and patients without colon inflammation (controls, n = 23) were analyzed by quantitative polymerase chain rection to measure expression of IL28A, IL28RA, and other related cytokines; biopsy samples were also analyzed by immunofluorescence to identify sources of IL28 production. IECs were isolated from patient tissues and incubated with IL28; signal transducer and activator of transcription 1 (STAT1) phosphorylation was measured by immunoblots and confocal imaging. RESULTS Lamina propria cells in colon tissues of patients with IBD, and mice with colitis, had increased expression of IL28 compared with controls; levels of IL28R were increased in the colonic epithelium of patients with IBD and mice with colitis. Administration of IL28 induced phosphorylation of STAT1 in primary human and mouse IECs, increasing with dose. Il28ra-/-, Irf3-/-, Irf3-/-Irf7-/-, as well as Stat1IEC-KO mice, developed more severe colitis after administration of dextran sulfate sodium than control mice, with reduced epithelial restitution. Il28ra-/- and Stat1IEC-KO mice also developed more severe colitis in response to oxazolone than control mice. We found IL28 to induce phosphorylation (activation) of STAT1 in epithelial cells, leading to their proliferation in organoid culture. Administration of IL28 to mice with induced colonic wounds promoted mucosal healing. CONCLUSIONS IL28 controls proliferation of IECs in mice with colitis and accelerates mucosal healing by activating STAT1. IL28 might be developed as a therapeutic agent for patients with IBD.
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Affiliation(s)
- Mircea T Chiriac
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany.
| | - Barbara Buchen
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Alexandra Wandersee
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Gheorghe Hundorfean
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Claudia Günther
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Yvonne Bourjau
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | | | - Benjamin Frey
- Department of Radiation Oncology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Arif B Ekici
- Core Unit Genomics, Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Christian Büttner
- Core Unit Genomics, Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Benno Weigmann
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Raja Atreya
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany; Ludwig Demling Endoscopy Center of Excellence, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Stefan Wirtz
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Christoph Becker
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Jürgen Siebler
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Markus F Neurath
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany; Ludwig Demling Endoscopy Center of Excellence, University of Erlangen-Nuremberg, Erlangen, Germany.
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Wang Y, Li T, Chen Y, Wei H, Sun R, Tian Z. Involvement of NK Cells in IL-28B-Mediated Immunity against Influenza Virus Infection. THE JOURNAL OF IMMUNOLOGY 2017. [PMID: 28637903 DOI: 10.4049/jimmunol.1601430] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
IL-28B is a member of the newly discovered type III IFN family and exhibits unique antiviral properties compared with other family members. NK cells play a critical role in defending against viruses; however, little is known about the role of IL-28B in NK cell function. In a mouse model of influenza A virus (mouse adapted influenza A/PR/8/34 strain) infection, long-term overexpression of IL-28B induced by hepatocyte-specific gene delivery exerted a strong antiviral effect in the presence of NK cells. In IL-28B-overexpressing wild-type mice, the percentages and absolute numbers of NK cells in the spleen, liver, and lung were markedly increased, with higher proliferation and accelerated NK cell maturation based on phenotypes staining with CD11b and CD27 or CD11b and KLRG1. Furthermore, the effect of IL-28B on NK cells was macrophage dependent, as confirmed in an in vitro coculture assay and in in vivo macrophage- or alveolar macrophage-depletion experiments. Transwell studies demonstrated that CFSE-labeled NK cell proliferation was driven, in a dose-dependent manner, by unknown soluble factor(s) secreted by IL-28B-stimulated alveolar macrophages, without requiring direct cell-cell contact. An understanding of the NK cell-promoting features of IL-28B will facilitate future clinical application of this cytokine.
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Affiliation(s)
- Yanshi Wang
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; and
| | - Tingting Li
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; and
| | - Yongyan Chen
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; and
| | - Haiming Wei
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; and
| | - Rui Sun
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; and .,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Zhigang Tian
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; and .,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
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Day PM, Thompson CD, Lowy DR, Schiller JT. Interferon Gamma Prevents Infectious Entry of Human Papillomavirus 16 via an L2-Dependent Mechanism. J Virol 2017; 91:e00168-17. [PMID: 28250129 PMCID: PMC5411602 DOI: 10.1128/jvi.00168-17] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 02/26/2017] [Indexed: 02/07/2023] Open
Abstract
In this study, we report that gamma interferon (IFN-γ) treatment, but not IFN-α, -β, or -λ treatment, dramatically decreased infection of human papillomavirus 16 (HPV16) pseudovirus (PsV). In a survey of 20 additional HPV and animal papillomavirus types, we found that many, but not all, PsV types were also inhibited by IFN-γ. Microscopic and biochemical analyses of HPV16 PsV determined that the antiviral effect was exerted at the level of endosomal processing of the incoming capsid and depended on the JAK2/STAT1 pathway. In contrast to infection in the absence of IFN-γ, where L1 proteolytic products are produced during endosomal capsid processing and L2/DNA complexes segregate from L1 in the late endosome and travel to the nucleus, IFN-γ treatment led to decreased L1 proteolysis and retention of L2 and the viral genome in the late endosome/lysosome. PsV sensitivity or resistance to IFN-γ treatment was mapped to the L2 protein, as determined with infectious hybrid PsV, in which the L1 protein was derived from an IFN-γ-sensitive HPV type and the L2 protein from an IFN-γ-insensitive type or vice versa.IMPORTANCE A subset of HPV are the causative agents of many human cancers, most notably cervical cancer. This work describes the inhibition of infection of multiple HPV types, including oncogenic types, by treatment with IFN-γ, an antiviral cytokine that is released from stimulated immune cells. Exposure of cells to IFN-γ has been shown to trigger the expression of proteins with broad antiviral effector functions, most of which act to prevent viral transcription or translation. Interestingly, in this study, we show that infection is blocked at the early step of virus entry into the host cell by retention of the minor capsid protein, L2, and the viral genome instead of trafficking into the nucleus. Thus, a novel antiviral mechanism for IFN-γ has been revealed.
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Affiliation(s)
- Patricia M Day
- Laboratory of Cellular Oncology, NCI, NIH, Bethesda, Maryland, USA
| | | | - Douglas R Lowy
- Laboratory of Cellular Oncology, NCI, NIH, Bethesda, Maryland, USA
| | - John T Schiller
- Laboratory of Cellular Oncology, NCI, NIH, Bethesda, Maryland, USA
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Yu Y, Wan P, Cao Y, Zhang W, Chen J, Tan L, Wang Y, Sun Z, Zhang Q, Wan Y, Zhu Y, Liu F, Wu K, Liu Y, Wu J. Hepatitis B Virus e Antigen Activates the Suppressor of Cytokine Signaling 2 to Repress Interferon Action. Sci Rep 2017; 7:1729. [PMID: 28496097 PMCID: PMC5431827 DOI: 10.1038/s41598-017-01773-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 03/31/2017] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) infection causes acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), and eventually hepatocellular carcinoma (HCC). The presence of hepatitis B e antigen (HBeAg) in the serum generally indicates ongoing viral replication and disease progression. However, the mechanism by which HBeAg regulates HBV infection remains unclear. Interferons (IFNs) are pleiotropic cytokines that participate in host innate immunity. After binding to receptors, IFNs activate the JAK/STAT pathway to stimulate expression of IFN-stimulated genes (ISGs), leading to induction of antiviral responses. Here, we revealed that HBeAg represses IFN/JAK/STAT signaling to facilitate HBV replication. Initially, HBeAg stimulates the expression of suppressor of cytokine signaling 2 (SOCS2). Subsequently, SOCS2 impairs IFN/JAK/STAT signaling through reducing the stability of tyrosine kinase 2 (TYK2), downregulating the expression of type I and III IFN receptors, attenuating the phosphorylation and nucleus translocation of STAT1. Finally, SOCS2 inhibits the expression of ISGs, which leads to the repression of IFN action and facilitation of viral replication. These results demonstrate an important role of HBeAg in the regulation of IFN action, and provide a possible molecular mechanism by which HBV resists the IFN therapy and maintains persistent infection.
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Affiliation(s)
- Yi Yu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.,Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Pin Wan
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Yanhua Cao
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Wei Zhang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Junbo Chen
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Li Tan
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Yan Wang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Zhichen Sun
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Qi Zhang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Yushun Wan
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Ying Zhu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Fang Liu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Kailang Wu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.
| | - Yingle Liu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.
| | - Jianguo Wu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.
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Syedbasha M, Egli A. Interferon Lambda: Modulating Immunity in Infectious Diseases. Front Immunol 2017; 8:119. [PMID: 28293236 PMCID: PMC5328987 DOI: 10.3389/fimmu.2017.00119] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 01/25/2017] [Indexed: 12/22/2022] Open
Abstract
Interferon lambdas (IFN-λs; IFNL1-4) modulate immunity in the context of infections and autoimmune diseases, through a network of induced genes. IFN-λs act by binding to the heterodimeric IFN-λ receptor (IFNLR), activating a STAT phosphorylation-dependent signaling cascade. Thereby hundreds of IFN-stimulated genes are induced, which modulate various immune functions via complex forward and feedback loops. When compared to the well-characterized IFN-α signaling cascade, three important differences have been discovered. First, the IFNLR is not ubiquitously expressed: in particular, immune cells show significant variation in the expression levels of and susceptibilities to IFN-λs. Second, the binding affinities of individual IFN-λs to the IFNLR varies greatly and are generally lower compared to the binding affinities of IFN-α to its receptor. Finally, genetic variation in the form of a series of single-nucleotide polymorphisms (SNPs) linked to genes involved in the IFN-λ signaling cascade has been described and associated with the clinical course and treatment outcomes of hepatitis B and C virus infection. The clinical impact of IFN-λ signaling and the SNP variations may, however, reach far beyond viral hepatitis. Recent publications show important roles for IFN-λs in a broad range of viral infections such as human T-cell leukemia type-1 virus, rotaviruses, and influenza virus. IFN-λ also potentially modulates the course of bacterial colonization and infections as shown for Staphylococcus aureus and Mycobacterium tuberculosis. Although the immunological processes involved in controlling viral and bacterial infections are distinct, IFN-λs may interfere at various levels: as an innate immune cytokine with direct antiviral effects; or as a modulator of IFN-α-induced signaling via the suppressor of cytokine signaling 1 and the ubiquitin-specific peptidase 18 inhibitory feedback loops. In addition, the modulation of adaptive immune functions via macrophage and dendritic cell polarization, and subsequent priming, activation, and proliferation of pathogen-specific T- and B-cells may also be important elements associated with infectious disease outcomes. This review summarizes the emerging details of the IFN-λ immunobiology in the context of the host immune response and viral and bacterial infections.
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Affiliation(s)
- Mohammedyaseen Syedbasha
- Applied Microbiology Research, Department of Biomedicine, University of Basel , Basel , Switzerland
| | - Adrian Egli
- Applied Microbiology Research, Department of Biomedicine, University of Basel, Basel, Switzerland; Clinical Microbiology, University Hospital Basel, Basel, Switzerland
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Zhang T, Essani K. Tanapoxvirus lacking the 15L gene inhibits melanoma cell growth in vitro by inducing interferon-λ1 release. Virus Genes 2017; 53:477-482. [DOI: 10.1007/s11262-017-1434-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 02/06/2017] [Indexed: 10/20/2022]
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Kelm NE, Zhu Z, Ding VA, Xiao H, Wakefield MR, Bai Q, Fang Y. The role of IL-29 in immunity and cancer. Crit Rev Oncol Hematol 2016; 106:91-8. [PMID: 27637354 PMCID: PMC7129698 DOI: 10.1016/j.critrevonc.2016.08.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 07/27/2016] [Accepted: 08/09/2016] [Indexed: 02/06/2023] Open
Abstract
Interleukin-29 (IL-29) is a new member of the recently discovered interferon λ (IFNλ) family. It is produced predominantly by maturing dendritic cells and macrophages. It has been implicated in numerous immunological responses and has shown antiviral activity similar to the Type I interferons, although its target cell population is more limited than the Type I interferons. In recent years, the role of IL-29 in the pathogenesis of various cancers has also been extensively studied. In this review, we will discuss the recent advances of IL-29 in immunological processes and the pathogenesis of various cancer.
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Affiliation(s)
- Noah E Kelm
- Department of Microbiology, Immunology & Pathology, Des Moines University, Des Moines, IA 50312, United States
| | - Ziwen Zhu
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, United States
| | - Vivi A Ding
- Department of Microbiology, Immunology & Pathology, Des Moines University, Des Moines, IA 50312, United States
| | - Huaping Xiao
- Department of Microbiology, Immunology & Pathology, Des Moines University, Des Moines, IA 50312, United States; The Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, China
| | - Mark R Wakefield
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, United States
| | - Qian Bai
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, United States
| | - Yujiang Fang
- Department of Microbiology, Immunology & Pathology, Des Moines University, Des Moines, IA 50312, United States; Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, United States.
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Chan HLY, Ahn SH, Chang TT, Peng CY, Wong D, Coffin CS, Lim SG, Chen PJ, Janssen HLA, Marcellin P, Serfaty L, Zeuzem S, Cohen D, Critelli L, Xu D, Wind-Rotolo M, Cooney E. Peginterferon lambda for the treatment of HBeAg-positive chronic hepatitis B: A randomized phase 2b study (LIRA-B). J Hepatol 2016; 64:1011-1019. [PMID: 26739688 DOI: 10.1016/j.jhep.2015.12.018] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 12/07/2015] [Accepted: 12/20/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Peginterferon lambda-1a (lambda) is a Type-III interferon, which, like alfa interferons, has antiviral activity in vitro against hepatitis B virus (HBV) and hepatitis C virus (HCV); however, lambda has a more limited extra-hepatic receptor distribution. This phase 2b study (LIRA-B) evaluated lambda in patients with chronic HBV infection. METHODS Adult HBeAg+ interferon-naive patients were randomized (1:1) to weekly lambda (180 μg) or peginterferon alfa-2a (alfa) for 48 weeks. The primary efficacy endpoint was HBeAg seroconversion at week 24 post-treatment; lambda non-inferiority was demonstrated if the 80% confidence interval (80% CI) lower bound was >-15%. RESULTS Baseline characteristics were balanced across groups (lambda N=80; alfa N=83). Early on-treatment declines in HBV-DNA and qHBsAg through week 24 were greater with lambda. HBeAg seroconversion rates were comparable for lambda and alfa at week 48 (17.5% vs. 16.9%, respectively); however lambda non-inferiority was not met at week 24 post-treatment (13.8% vs. 30.1%, respectively; lambda vs. alfa 80% CI lower bound -24%). Results for other key secondary endpoints (virologic, serologic, biochemical) and post hoc combined endpoints (HBV-DNA <2000 IU/ml plus HBeAg seroconversion or ALT normalization) mostly favored alfa. Overall adverse events (AE), serious AE, and AE-discontinuation rates were comparable between arms but AE-spectra differed (more cytopenias, flu-like, and musculoskeletal symptoms observed with alfa, more ALT flares and bilirubin elevations seen with lambda). Most on-treatment flares occurred early (weeks 4-12), associated with HBV-DNA decline; all post-treatment flares were preceded by HBV-DNA rise. CONCLUSIONS On-treatment, lambda showed greater early effects on HBV-DNA and qHBsAg, and comparable serologic/virologic responses at end-of-treatment. However, post-treatment, alfa-associated HBeAg seroconversion rates were higher, and key secondary results mostly favored alfa. ClinicalTrials.gov number: NCT01204762.
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Affiliation(s)
- Henry L Y Chan
- The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Sang Hoon Ahn
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | | | | | - David Wong
- Toronto Western Hospital University Health Network, Toronto, ON, Canada
| | - Carla S Coffin
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | | | - Pei-Jer Chen
- National Taiwan University Hospital, Taipei, Taiwan
| | - Harry L A Janssen
- Erasmus Medical Center, Rotterdam, Netherlands; University Health Network, Toronto, Canada
| | - Patrick Marcellin
- Hôpital Beaujon and INSERM CRI Université Paris Diderot, Clichy, France
| | | | - Stefan Zeuzem
- Johann Wolfgang Goethe University, Frankfurt, Germany
| | - David Cohen
- Bristol-Myers Squibb Research and Development, Wallingford, CT, USA
| | - Linda Critelli
- Bristol-Myers Squibb Research and Development, Wallingford, CT, USA
| | - Dong Xu
- Bristol-Myers Squibb Research and Development, Wallingford, CT, USA
| | - Megan Wind-Rotolo
- Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA
| | - Elizabeth Cooney
- Bristol-Myers Squibb Research and Development, Wallingford, CT, USA.
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Xu F, Yu Y, Yang YH, Liu H, Wang J. Clinical significance of IL-28B expression in HBV related hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2016; 24:1812-1818. [DOI: 10.11569/wcjd.v24.i12.1812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the expression of interleukin-28B (IL-28B) gene in human HBV related hepatocellular carcinoma, and analyze the relationship between IL-28B expression and clinicopathologic features of HBV related hepatocellular carcinoma.
METHODS: Serum samples were collected from 96 patients with HBV related hepatocellular carcinoma and 84 patients with HBV related benign hepatic nodules. Serum levels of IL-28B were measured by enzyme-linked immunosorbant assay (ELISA). The expression of IL-28B in HBV related hepatocellular carcinoma tissues was detected by immunohistochemistry.
RESULTS: The mean level of serum IL-28B was significantly higher in the HBV related hepatocellular carcinoma group than in the HBV related benign hepatic nodules group. Immunohistochemistry showed that the positive expression rate of IL-28B was significantly higher in HBV related hepatocellular carcinoma tissues than in HBV related hepatic benign nodule tissues (83.33% vs 66.66%, P < 0.05). IL-28B expression was not correlated with age, gender, HBV DNA, or tumor differentiation, but it was significantly related to AFP, tumor maximum diameter and clinical TNM stage (χ2 = 6.653, 6.732, and 8.642, P < 0.05 for all).
CONCLUSION: The level of IL-28B has certain value in the diagnosis of HBV related hepatocellular carcinoma. The expression of IL-28B in HBV related hepatocellular carcinoma tissues significantly increases, which correlates with AFP, tumor maximum diameter and clinical TNM stage. The dysregulated expression of IL-28B might participate in the genesis and development of HBV related hepatocellular carcinoma.
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Heidari Z, Moudi B, Mahmoudzadeh-Sagheb H, Hashemi M. The Correlation Between Interferon Lambda 3 Gene Polymorphisms and Susceptibility to Hepatitis B Virus Infection. HEPATITIS MONTHLY 2016; 16:e34266. [PMID: 27226800 PMCID: PMC4875561 DOI: 10.5812/hepatmon.34266] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Revised: 01/31/2016] [Accepted: 02/08/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cytokines are proteins that mediate innate and adaptive immunity responses. It is hypothesized that interferon lambda 3 (IFNL3) levels can influence the outcome of chronic hepatitis B virus (HBV) infection. Polymorphisms in IFN genes have been associated with response to infection. OBJECTIVES This study was carried-out to investigate the association of IFNL3 gene polymorphisms (rs12979860 and rs8099917) with HBV susceptibility, in chronic HBV-infected patients. PATIENTS AND METHODS In this case-control study, we determined IFNL3 single nucleotide polymorphisms (SNPs) (rs12979860 and rs8099917) in 221 individuals, with chronic HBV infection, and 200 healthy individuals, who were voluntary blood donors, with negative test for HBV. Alleles and genotypes analyses were performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS The frequencies of the rs12979860 and rs8099917 genotypes were not significantly different between the HBV-infected and the control groups (CC:CT:TT of 30.3%:48.0%:21.7% vs. 33.0%:49.0%:18.0%, P > 0.05, and GG:GT:TT of 5.8%:39.4%:54.8% vs. 5.0%:41.0%:54.0%, P > 0.05, respectively). Also, the frequencies of the alleles were not significantly different between both groups (C:T of 54.3%:45.7% vs. 57.5%:42.5%, P > 0.05, and G:T of 25.6%:74.4% vs. 25.5%:74.5%, P > 0.05, respectively) and the chronic HBV infection. There were no significant differences between patients, with at least one rs12979860C and or rs8099917T alleles compared to the healthy controls (rs12979860: CT + CC:TT, OR = 1.26, 95%CI = 0.78 - 2.04, P = 0.341 and rs8099917: GT + TT:GG, OR = 1.03, 95%CI = 0.70 - 1.51, P = 0.877, respectively). CONCLUSIONS Our study showed no correlation between rs12979860 and rs8099917 SNPs and chronic HBV infection. Further studies, with larger sample sizes and different ethnicities, are necessary to validate our findings.
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Affiliation(s)
- Zahra Heidari
- Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, IR Iran
- Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, IR Iran
| | - Bita Moudi
- Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, IR Iran
- Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, IR Iran
- Corresponding Author: Bita Moudi, Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, IR Iran. Tel: +98-5433295794, Fax: +98-5433295794, E-mail:
| | - Hamidreza Mahmoudzadeh-Sagheb
- Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, IR Iran
- Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, IR Iran
| | - Mohammad Hashemi
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, IR Iran
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, IR Iran
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Microbial pathogenesis and type III interferons. Cytokine Growth Factor Rev 2016; 29:45-51. [PMID: 26987613 PMCID: PMC4899229 DOI: 10.1016/j.cytogfr.2016.02.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 02/19/2016] [Accepted: 02/22/2016] [Indexed: 01/22/2023]
Abstract
The innate immune system possesses a multitude of pathways to sense and respond to microbial pathogens. One such family are the interferons (IFNs), a family of cytokines that are involved in several cellular functions. Type I IFNs are appreciated to be important in several viral and bacterial diseases, while the recently identified type III IFNs (IFNL1, IFNL2, IFNL3, IFNL4) have been studied primarily in the context of viral infection. Viral and bacterial infections however are not mutually exclusive, and often the presence of a viral pathogen increases the pathogenesis of bacterial infection. The role of type III IFN in bacterial and viral-bacterial co-infections has just begun to be explored. In this mini review we discuss type III IFN signaling and its role in microbial pathogenesis with an emphasis on the work that has been conducted with bacterial pathogens.
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Erturk K, Tastekin D, Serilmez M, Bilgin E, Bozbey HU, Vatansever S. Clinical significance of serum interleukin-29, interleukin-32, and tumor necrosis factor alpha levels in patients with gastric cancer. Tumour Biol 2016; 37:405-12. [PMID: 26219901 DOI: 10.1007/s13277-015-3829-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 07/20/2015] [Indexed: 01/11/2023] Open
Abstract
Many studies suggested that cytokines interleukin (IL)-29, IL-32, and tumor necrosis factor alpha (TNF-α) are implicated in the pathogenesis of malignancies. The purpose of this study was to determine the clinical significance of the serum levels of IL-29, IL-32, and TNF-α in gastric cancer (GC) patients. Fifty-eight GC patients and 20 age- and sex-matched healthy controls were enrolled into this study. The median age at diagnosis was 59.5 years (range 32-82 years). Tumor localization of the majority of the patients was antrum (n = 42, 72.4 %), and tumor histopathology of the majority of the patients was diffuse (n = 43, 74.1 %). The majority of the patients had stage IV disease (n = 41, 70.7 %). Thirty-six (62.1 %) patients had lymph node involvement. The median follow-up time was 66 months (range 1 to 97.2 months). The baseline serum IL-29 concentrations were not different between patients and controls (p = 0.627). The baseline serum IL-32 and TNF-α concentrations of the GC patients were significantly higher (for IL-32, p = 0.014; for TNF-α, p = 0.001). Gender, localization, histopathology, tumor, and lymph node involvement were not found to be correlated with serum IL-29, IL-32, and TNF-α concentrations (p > 0.05). Patients without metastasis (p = 0.01) and patients who responded to chemotherapy (p = 0.04) had higher serum IL-29 concentrations. Patients older than 60 years had higher serum IL-32 (p = 0.002). Serum IL-29, IL-32, and TNF-α levels were not associated with outcome (p = 0.30, p = 0.51, and p = 0.41, respectively). In conclusion, serum levels of IL-32 and TNF-α may be diagnostic markers, and serum IL-29 levels may be associated with good prognosis in patients with GC.
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Affiliation(s)
- Kayhan Erturk
- Institute of Oncology, Istanbul University, Capa, 34093, Istanbul, Turkey.
| | - Didem Tastekin
- Institute of Oncology, Istanbul University, Capa, 34093, Istanbul, Turkey
| | - Murat Serilmez
- Institute of Oncology, Istanbul University, Capa, 34093, Istanbul, Turkey
| | - Elif Bilgin
- Institute of Oncology, Istanbul University, Capa, 34093, Istanbul, Turkey
| | - Hamza Ugur Bozbey
- Institute of Oncology, Istanbul University, Capa, 34093, Istanbul, Turkey
| | - Sezai Vatansever
- Institute of Oncology, Istanbul University, Capa, 34093, Istanbul, Turkey
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Aboulnasr F, Hazari S, Nayak S, Chandra PK, Panigrahi R, Ferraris P, Chava S, Kurt R, Song K, Dash A, Balart LA, Garry RF, Wu T, Dash S. IFN-λ Inhibits MiR-122 Transcription through a Stat3-HNF4α Inflammatory Feedback Loop in an IFN-α Resistant HCV Cell Culture System. PLoS One 2015; 10:e0141655. [PMID: 26657215 PMCID: PMC4686105 DOI: 10.1371/journal.pone.0141655] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 10/12/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND HCV replication in persistently infected cell culture remains resistant to IFN-α/RBV combination treatment, whereas IFN-λ1 induces viral clearance. The antiviral mechanisms by which IFN-λ1 induces sustained HCV clearance have not been determined. AIM To investigate the mechanisms by which IFN-λ clears HCV replication in an HCV cell culture model. METHODS IFN-α sensitive (S3-GFP) and resistant (R4-GFP) cells were treated with equivalent concentrations of either IFN-α or IFN-λ. The relative antiviral effects of IFN-α and IFN-λ1 were compared by measuring the HCV replication, quantification of HCV-GFP expression by flow cytometry, and viral RNA levels by real time RT-PCR. Activation of Jak-Stat signaling, interferon stimulated gene (ISG) expression, and miRNA-122 transcription in S3-GFP and R4-GFP cells were examined. RESULTS We have shown that IFN-λ1 induces HCV clearance in IFN-α resistant and sensitive replicon cell lines in a dose dependent manner through Jak-Stat signaling, and induces STAT 1 and STAT 2 activation, ISRE-luciferase promoter activation and ISG expression. Stat 3 activation is also involved in IFN-λ1 induced antiviral activity in HCV cell culture. IFN-λ1 induced Stat 3 phosphorylation reduces the expression of hepatocyte nuclear factor 4 alpha (HNF4α) through miR-24 in R4-GFP cells. Reduced expression of HNF4α is associated with decreased expression of miR-122 resulting in an anti-HCV effect. Northern blot analysis confirms that IFN-λ1 reduces miR-122 levels in R4-GFP cells. Our results indicate that IFN-λ1 activates the Stat 3-HNF4α feedback inflammatory loop to inhibit miR-122 transcription in HCV cell culture. CONCLUSIONS In addition to the classical Jak-Stat antiviral signaling pathway, IFN-λ1 inhibits HCV replication through the suppression of miRNA-122 transcription via an inflammatory Stat 3-HNF4α feedback loop. Inflammatory feedback circuits activated by IFNs during chronic inflammation expose non-responders to the risk of hepatocellular carcinoma.
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Affiliation(s)
- Fatma Aboulnasr
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Sidhartha Hazari
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Satyam Nayak
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Partha K. Chandra
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Rajesh Panigrahi
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Pauline Ferraris
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Srinivas Chava
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Ramazan Kurt
- Department of Medicine, Division of Gastroenterology and Hepatology
| | - Kyongsub Song
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Asha Dash
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Luis A. Balart
- Department of Medicine, Division of Gastroenterology and Hepatology
| | - Robert F. Garry
- Microbiology and Immunology Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Tong Wu
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Srikanta Dash
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
- Department of Medicine, Division of Gastroenterology and Hepatology
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Alase AA, El-Sherbiny YM, Vital EM, Tobin DJ, Turner NA, Wittmann M. IFNλ Stimulates MxA Production in Human Dermal Fibroblasts via a MAPK-Dependent STAT1-Independent Mechanism. J Invest Dermatol 2015; 135:2935-2943. [PMID: 26288353 DOI: 10.1038/jid.2015.317] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 06/17/2015] [Accepted: 07/11/2015] [Indexed: 02/07/2023]
Abstract
IFNλ is important for epidermal defense against viruses. It is produced by, and acts on, keratinocytes, whereas fibroblasts were previously considered to be unresponsive to this type III IFN. Herein we report findings revealing cell type-specific differences in IFNλ signaling and function in skin resident cells. In dermal fibroblasts, IFNλ induced the expression of myxovirus protein A (MxA), a potent antiviral factor, but not other IFN signature genes as it does in primary keratinocytes. In contrast to its effect on keratinocytes, IFNλ did not phosphorylate signal transducer and activator of transcription 1 in fibroblasts, but instead activated mitogen activated protein kinases (MAPK). Accordingly, inhibition of MAPK activation (p38 and p42/44) blocked the expression of MxA protein in fibroblasts but not in keratinocytes. Functionally, IFNλ inhibited proliferation in keratinocytes but not in fibroblasts. Moreover, IFNλ upregulated the expression of Tumor growth factor beta 1 (TGFβ1)-induced collagens in fibroblasts. Taken together, our findings identify primary human dermal fibroblasts as responder cells to IFNλ. Our study shows cutaneous cell type-specific IFN signaling and suggests that IFNλ, although important for epidermal antiviral competence, may also have a regulatory role in the dermal compartment balancing type I IFN-induced inhibition of tissue repair processes.
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Affiliation(s)
- Adewonuola A Alase
- Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, Bradford, UK.
| | - Yasser M El-Sherbiny
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Faculty of Medicine and Health, University of Leeds, Leeds, UK; Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Edward M Vital
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Faculty of Medicine and Health, University of Leeds, Leeds, UK
| | - Desmond J Tobin
- Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, Bradford, UK
| | - Neil A Turner
- Division of Cardiovascular and Diabetes Research, Leeds Institute for Cardiovascular and Diabetes Research (LICAMM), Faculty of Medicine and Health, University of Leeds, Leeds, UK
| | - Miriam Wittmann
- Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, Bradford, UK; Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Faculty of Medicine and Health, University of Leeds, Leeds, UK; Department of Dermatology, Bradford Teaching Hospitals NHS Foundation Trust, St Luke's Hospital, Bradford, UK; Leeds Musculoskeletal Biomedical Research Unit, National Institute of Health Research (NIHR), Chapel Allerton Hospital, Leeds, UK
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Lin M, Yu HP. Dexamethasone decreases IL-29 expression in house dust mite-stimulated human bronchial epithelial cells. JOURNAL OF HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY. MEDICAL SCIENCES = HUA ZHONG KE JI DA XUE XUE BAO. YI XUE YING DE WEN BAN = HUAZHONG KEJI DAXUE XUEBAO. YIXUE YINGDEWEN BAN 2015; 35:823-827. [PMID: 26670431 DOI: 10.1007/s11596-015-1513-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 11/02/2015] [Indexed: 12/12/2022]
Abstract
The aim of this study was to explore the effect of IL-29 on the progression of airway allergic disease by detecting the level of IL-29 in airway allergic cell models stimulated by house dust mite (HDM) in the presence or absence of dexamethasone (DEX). The same batch of human bronchial epithelial cells in exponential growth phase was randomly divided into five groups: blank group (A), 300 ng/mL HDM group (B), 1000 ng/mL HDM group (C), 3000 ng/mL HDM group (D), and 300 ng/mL HDM+100 ng/mL DEX group (E). The IL-29 mRNA expression was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The IL-29 protein expression in cell suspension was detected by ELISA. The results showed that after stimulation with HDM for 24 h, the expression of IL-29 was increased significantly, and after co-stimulation with HDM and DEX for 24 h, the expression of IL-29 in group E was significantly lower than that in the groups stimulated by HDM alone but higher than that in the group A. The differences between the different groups were significant (F=132.957, P<0.01). Additionally, the higher the concentration of HDM was, the more significant the increase in the IL-29 expression was. In conclusion, IL-29 may play a role in the progression of airway allergic disease including asthma.
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Affiliation(s)
- Mei Lin
- Southern Medical University, Guangzhou, 510515, China
- Wuhan Third Hospital, Wuhan, 430060, China
| | - Hua-Peng Yu
- Southern Medical University, Guangzhou, 510515, China.
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Bu X, Wang M, Zhang J, Liu J, Jia L, Liang B, Yan Y. Recombinant adenovirus expressing hIFN-λ1 inhibits gastric adenocarcinoma cell line SGC-7901 proliferation. Oncol Lett 2015; 11:287-292. [PMID: 26870205 DOI: 10.3892/ol.2015.3890] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 09/24/2015] [Indexed: 01/03/2023] Open
Abstract
The aim of the present study is to investigate the effect of a recombinant plasmid adenovirus (pAd) expressing human interferon-λ1 (hIFN-λ1) on the proliferation of the gastric adenocarcinoma cell line SGC-7901. For this purpose, human gastric adenocarcinoma SGC-7901 cells were infected with recombinant pAd-hIFN-λ1, pAd-LacZ and phosphate-buffered saline (PBS), respectively, and the subsequent effects on the proliferation of the infected cells were compared. Cell proliferation was evaluated by MTT assay, while mRNA and protein expression of hIFN-λ1 were detected by reverse transcription-polymerase chain reaction analysis and immunofluorescence assay, respectively. In addition, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay and flow cytometry were conducted to analyze the rate of cell apoptosis. The results indicated that the proliferation of gastric adenocarcinoma SGC-7901 cells was significantly inhibited by pAd-hIFN-λ1. Furthermore, the apoptosis rate and the mRNA and protein expression levels of hIFN-λ1 were higher in pAd-hIFN-λ1-transfected cells, compared with the pAd-LacZ and PBS control groups. In conclusion, recombinant pAd-hIFN-λ1 induced the expression of hIFN-λ1 in gastric adenocarcinoma SGC-7901 cells, and significantly inhibited cell proliferation by promoting apoptosis in these cancer cells.
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Affiliation(s)
- Xuefeng Bu
- Department of General Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Mubin Wang
- Department of Surgical Medicine, Clinical Medicine College of Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jie Zhang
- Department of Surgical Medicine, Clinical Medicine College of Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jun Liu
- Department of Surgical Medicine, Clinical Medicine College of Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Lijuan Jia
- Department of Internal Medicine, Clinical Medicine College of Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Bing Liang
- Department of Internal Medicine, Clinical Medicine College of Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Yulan Yan
- Department of Respiratory Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
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Lu Y, Li L, Chen W, Wu M. Enhanced Anti-Tumor (Anti-Proliferation) Activity of Recombinant Human Interleukin-29 (IL-29) Mutants Using Site-Directed Mutagenesis Method. Appl Biochem Biotechnol 2015; 177:1164-75. [PMID: 26277192 DOI: 10.1007/s12010-015-1804-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 08/10/2015] [Indexed: 12/31/2022]
Abstract
Interferon (IFN)-λ, also known as IL-28A, IL-28B, or IL-29, is a new type III IFN, which shares many functional characteristics with type I IFN (α/β). Currently, IFN-α is used in the treatment of certain forms of cancer with severe adverse effects. Some researches had stated that IFN-λs induced a similar but restricted growth inhibition of tumor cells relative to IFN-α; moreover, mutations of IFN-λs could strongly impact its biological properties. In this study, three hIL-29 mutants (K33R, R35K, and K33R/R35K) were generated by site-directed mutagenesis and efficiently expressed in Pichia pastoris GS115, which have considerable abilities to inhibit the growth of BEL-7402, HCT-8, and SGC-7901 tumor cells in vitro. The results showed that these mutants (K33R, R35K, and K33R/R35K) exhibited a significantly enhanced anti-proliferation activity against these tumor cells, compared with native hIL-29 in vitro. Further assay in vitro indicated that superior to K33R and R35K, K33R/R35K had a significant increase in anti-tumor activity compared with IFN-α2b, which suggested that the K33R/R35K could make improvement for the effectiveness of native hIL-29 in clinic and could be used as a potentially powerful candidate for cancer immunotherapy.
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Affiliation(s)
- Yuan Lu
- School of Pharmaceutical Sciences, Jiangnan University, No. 1800 Lihu Road, Wuxi, 214122, China.
| | - Liyun Li
- School of Biotechnology, Jiangnan University, No. 1800 Lihu Road, Wuxi, 214122, China.
| | - Wei Chen
- Wuxi Medical School, Jiangnan University, No. 1800 Lihu Road, Wuxi, 214122, China.
| | - Minchen Wu
- Wuxi Medical School, Jiangnan University, No. 1800 Lihu Road, Wuxi, 214122, China.
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Choobin H, Bamdad T, Soleimanjahi H, Razavinikoo H. Antitumor effect of mIFN-λ3 in C57BL/6 mice model for papilloma tumors. Mol Biol 2015. [DOI: 10.1134/s0026893315050064] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Chen X, Zhu B, Luo Y, Zhang D, Zhang L, Zhu H, Hao C, Guo Y, Liu H. Interleukin-28B Plays a Therapeutic Role on Mouse U14 Cervical Cancer Cells by Down-Regulating CD4+CD25+FoxP3+Regulatory T Cells In Vivo. Int J Gynecol Cancer 2015; 25:1369-76. [PMID: 26270121 DOI: 10.1097/igc.0000000000000528] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
AIM To investigate the immunotherapeutic effectiveness of adenoviral vector expressing mouse interleukin (IL)-28B (Ad-mIL-28B) against cervical cancer and its mechanism. METHOD U14 cervical cancer cell-bearing mice were treated with Ad-mIL-28B. Meanwhile, whole cell vaccine was prepared by repeated freezing and thawing U14 cells. Then CD4⁺CD25⁺FoxP3⁺regulatory T (Treg) cells were evaluated by flow cytometry. Tumor volume and metastasis in BALB/c and C57BL/6j mice were detected. RESULTS Ad-mIL-28B treatment significantly decreased the number of CD4⁺CD25⁺FoxP3⁺Treg cells. Subsequently, there was a significant decrease in the size of tumor tissue and the numbers of heteromorphic tumor cells. The tumor metastasis in the lung and liver of the Ad-mIL-28B group also decreased. However, there was no therapeutic effect observed for whole cell vaccine on U14 tumor-bearing mice. CONCLUSION Interleukin-28B can inhibit the growth and metastasis of cervical cancer in U14 tumor-bearing mice by down-regulating Treg cells.
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Affiliation(s)
- Xiaoyun Chen
- *Department of Gynecology and Obstetrics, the Second Affiliated Hospital of Lanzhou University, Lanzhou, Gansu Province, China; Institutes of †Pathogen Biology and ‡Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province, China; §Institute of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province, China; and ∥Department of Obstetrics and Gynecology, Gansu Provincial Hospital, Lanzhou, Gansu Province, China
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Travar M, Petkovic M, Verhaz A. Type I, II, and III Interferons: Regulating Immunity to Mycobacterium tuberculosis Infection. Arch Immunol Ther Exp (Warsz) 2015; 64:19-31. [PMID: 26362801 DOI: 10.1007/s00005-015-0365-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 07/22/2015] [Indexed: 01/18/2023]
Abstract
Interferons (IFNs) are cytokines released by host cells in response to the presence of pathogens or tumor cells. The aim of this review was to present the previously known and new findings about the role of interferons type I and II, and recently discovered type III in Mycobacterium tuberculosis (M. tuberculosis) infection control. Infection of various cell types with M. tuberculosis induce both IFN-α and IFN-β synthesis. The majority of the studies support the findings that IFN type I actually promotes infection with M. tuberculosis. It has been well establish that IFN-γ has protective function against M. tuberculosis and the other mycobacteria and that the primary source of this cytokine are CD4(+) and CD8(+) T cells. Recently, it has been shown that also the innate lymphocytes, γδ T cells, natural killer (NK) T cells, and NK cells can also be the source of IFN-γ in response to mycobacterial infection. Several studies have shown that CD4(+) T cells protect mice against M. tuberculosis independently of IFN-γ. The balance between IFN-γ and different cytokines such as IL-10 and other Th2 cell cytokines is likely to influence disease outcome. Type I IFN appears to be detrimental through at least three separate, but overlapping, type I IFN-mediated mechanisms: induction of excessive apoptosis, specific suppression of Th1 and IFN-γ responses, and dampening of the immune response by strong IL-10 induction. Recently it has been found that M. tuberculosis infection in A549 lung epithelial cells stimulate up-regulation of IFN-λ genes in vitro. IFN-λs also have a role in modulation of Th1/Th2 response. IFN-λs are not essential for M. tuberculosis infection control, but can give some contribution in immune response to this pathogen.
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Affiliation(s)
- Maja Travar
- Department of Microbiology, University Hospital Clinical Centre Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina. .,Department of Microbiology and Immunology, Faculty of Medicine, Banja Luka University, Banja Luka, Republic of Srpska, Bosnia and Herzegovina.
| | - Miroslav Petkovic
- Department of Microbiology and Immunology, Faculty of Medicine, Banja Luka University, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Antonija Verhaz
- Clinic for Infectious Diseases, University Hospital Clinical Centre Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
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Torres C, Linares A, Alejandre MJ, Palomino-Morales RJ, Caba O, Prados J, Aránega A, Delgado JR, Irigoyen A, Martínez-Galán J, Ortuño FM, Rojas I, Perales S. Prognosis Relevance of Serum Cytokines in Pancreatic Cancer. BIOMED RESEARCH INTERNATIONAL 2015; 2015:518284. [PMID: 26346854 PMCID: PMC4539422 DOI: 10.1155/2015/518284] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 01/05/2015] [Accepted: 01/12/2015] [Indexed: 02/06/2023]
Abstract
The overall survival of patients with pancreatic ductal adenocarcinoma is extremely low. Although gemcitabine is the standard used chemotherapy for this disease, clinical outcomes do not reflect significant improvements, not even when combined with adjuvant treatments. There is an urgent need for prognosis markers to be found. The aim of this study was to analyze the potential value of serum cytokines to find a profile that can predict the clinical outcome in patients with pancreatic cancer and to establish a practical prognosis index that significantly predicts patients' outcomes. We have conducted an extensive analysis of serum prognosis biomarkers using an antibody array comprising 507 human cytokines. Overall survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox's proportional hazard models were used to analyze prognosis factors. To determine the extent that survival could be predicted based on this index, we used the leave-one-out cross-validation model. The multivariate model showed a better performance and it could represent a novel panel of serum cytokines that correlates to poor prognosis in pancreatic cancer. B7-1/CD80, EG-VEGF/PK1, IL-29, NRG1-beta1/HRG1-beta1, and PD-ECGF expressions portend a poor prognosis for patients with pancreatic cancer and these cytokines could represent novel therapeutic targets for this disease.
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Affiliation(s)
- Carolina Torres
- Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain
| | - Ana Linares
- Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain
| | - Maria José Alejandre
- Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain
| | | | - Octavio Caba
- Department of Health Sciences, University of Jaen, 23071 Jaen, Spain
| | - Jose Prados
- Department of Human Anatomy and Embryology, University of Granada, 18012 Granada, Spain
| | - Antonia Aránega
- Department of Human Anatomy and Embryology, University of Granada, 18012 Granada, Spain
| | - Juan R. Delgado
- Oncology Service, Virgen de las Nieves Hospital, 18014 Granada, Spain
| | - Antonio Irigoyen
- Oncology Service, Virgen de las Nieves Hospital, 18014 Granada, Spain
| | | | - Francisco M. Ortuño
- Department of Computer Architecture and Computer Technology (CITIC-UGR), University of Granada, 18071 Granada, Spain
| | - Ignacio Rojas
- Department of Computer Architecture and Computer Technology (CITIC-UGR), University of Granada, 18071 Granada, Spain
| | - Sonia Perales
- Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain
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