Interferon type I
Interferon Type I (α/β/δ...) | |||||||||||
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Identifiers | |||||||||||
Symbol | Interferons | ||||||||||
Pfam | PF00143 | ||||||||||
InterPro | IPR000471 | ||||||||||
SMART | SM00076 | ||||||||||
PROSITE | PDOC00225 | ||||||||||
CATH | 1au1 | ||||||||||
SCOP2 | 1au1/SCOPe/SUPFAM | ||||||||||
CDD | cd00095 | ||||||||||
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Thetype-I interferons(IFN) arecytokineswhich play essential roles ininflammation,immunoregulation,tumor cells recognition, andT-cellresponses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cytoband over approximately 400 kb including coding genes for IFNα (IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17andIFNA21), IFNω (IFNW1), IFNɛ (IFNE), IFNк (IFNK) and IFNβ (IFNB1), plus 11 IFN pseudogenes.[1]
Interferons bind tointerferon receptors.All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor (IFNAR) that consists ofIFNAR1andIFNAR2chains.
Type I IFNs are found in all mammals, and homologous (similar) molecules have been found in birds, reptiles, amphibians and fish species.[2][3]
Sources and functions
[edit]IFN-α and IFN-β are secreted by many cell types includinglymphocytes(NK cells,B-cellsandT-cells), macrophages, fibroblasts, endothelial cells, osteoblasts and others. They stimulate bothmacrophagesand NK cells to elicit an anti-viral response, involving IRF3/IRF7 antiviral pathways,[4]and are also active againsttumors.Plasmacytoid dendritic cellshave been identified as being the most potent producers of type I IFNs in response to antigen, and have thus been coined natural IFN producing cells.[citation needed]
IFN-ω is released byleukocytesat the site of viral infection or tumors.[citation needed]
IFN-α acts as apyrogenicfactor by altering the activity of thermosensitiveneuronsin thehypothalamusthus causing fever. It does this by binding toopioid receptorsand eliciting the release ofprostaglandin-E2(PGE2).[citation needed]
A similar mechanism is used by IFN-α to reduce pain; IFN-α interacts with the μ-opioid receptor to act as ananalgesic.[5]
In mice, IFN-β inhibits immune cell production of growth factors, thereby slowing tumor growth, and inhibits other cells from producing vessel-producing growth factors, thereby blockingtumor angiogenesisand hindering the tumour from connecting into the blood vessel system.[6]
In both mice and human, negative regulation of type I interferon signaling is known to be important. Few endogenous regulators have been found to elicit this important regulatory function, such as SOCS1 andAryl Hydrocarbon Receptor Interacting Protein(AIP).[7]
Mammalian types
[edit]The mammalian types are designated IFN-α (alpha), IFN-β (beta), IFN-κ (kappa), IFN-δ (delta), IFN-ε (epsilon), IFN-τ (tau), IFN-ω (omega), and IFN-ζ (zeta, also known as limitin).[8][9]Of these types, IFN-α, IFN -ω, and IFN-τ can work across species.[10]
IFN-α
[edit]The IFN-α proteins are produced mainly byplasmacytoid dendritic cells(pDCs). They are mainly involved in innate immunity against viral infection. The genes responsible for their synthesis come in 13 subtypes that are calledIFNA1,IFNA2,IFNA4,IFNA5,IFNA6,IFNA7,IFNA8,IFNA10,IFNA13,IFNA14,IFNA16,IFNA17,IFNA21.These genes are found together in a cluster on chromosome 9.
IFN-α is also made synthetically asmedicationin hairy cell leukemia. TheInternational Nonproprietary Name(INN) for the product isinterferon alfa.Therecombinanttype isinterferon alfacon-1.Thepegylatedtypes arepegylated interferon alfa-2aandpegylated interferon alfa-2b.
Recombinant feline interferon omegais a form ofcatIFN-α (not ω) for veterinary use.[10]
IFN-β
[edit]The IFN-β proteins are produced in large quantities byfibroblasts.They have antiviral activity that is involved mainly in innate immune response. Two types of IFN-β have been described, IFN-β1 (IFNB1) and IFN-β3 (IFNB3)[11](a gene designated IFN-β2 is actuallyIL-6).
IFN-ε, -κ, -τ, -δ and -ζ
[edit]IFN-ε, -κ, -τ, and -ζ appear, at this time, to come in a single isoform in humans,IFNK.Only ruminants encode IFN-τ, a variant of IFN-ω. So far, IFN-ζ is only found in mice, while a structural homolog, IFN-δ is found in a diverse array of non-primate and non-rodent placental mammals. Most but not all placental mammals encode functional IFN-ε and IFN-κ genes.[citation needed].
IFN-ω
[edit]IFN-ω, although having only one functional form described to date (IFNW1), has severalpseudogenes:IFNWP2,IFNWP4,IFNWP5,IFNWP9,IFNWP15,IFNWP18,andIFNWP19in humans. Many non-primate placental mammals express multiple IFN-ω subtypes.
IFN-ν
[edit]This subtype of type I IFN was recently described as a pseudogene in human, but potentially functional in the domestic cat genome. In all other genomes of non-feline placental mammals, IFN-ν is a pseudogene; in some species, the pseudogene is well preserved, while in others, it is badly mutilated or is undetectable. Moreover, in the cat genome, the IFN-ν promoter is deleteriously mutated. It is likely that the IFN-ν gene family was rendered useless prior to mammalian diversification. Its presence on the edge of the type I IFN locus in mammals may have shielded it from obliteration, allowing its detection.[citation needed]
Interferon type I in cancer
[edit]Therapeutics
[edit]From the 1980s onward, members of type-I IFN family have been the standard care as immunotherapeutic agents in cancer therapy. In particular, IFNα has been approved by theUS Food and Drug Administration(FDA) for cancer. To date, pharmaceutical companies produce several types of recombinant andpegylatedIFNα for clinical use; e.g., IFNα2a (Roferon-A,Roche), IFNα2b (Intron-A,Schering-Plough) and pegylated IFNα2b (Sylatron, Schering Corporation) for treatment ofhairy cell leukemia,melanoma,renal cell carcinoma,Kaposi's sarcoma,multiple myeloma,follicular and non-Hodgkin lymphoma, andchronic myelogenous leukemia.Human IFNβ (Feron,Toray ltd.) has also been approved in Japan to treatglioblastoma,medulloblastoma,astrocytoma,andmelanoma.[1]
Copy number alteration of the interferon gene cluster in cancer
[edit]A large individual patient data meta-analysis using 9937 patients obtained from cBioportal indicates that copy number alteration of the IFN gene cluster is prevalent among 24cancertypes. Notably deletion of this cluster is significantly associated with increased mortality in many cancer types particularlyuterus,kidney,andbraincancers. The Cancer Genome AtlasPanCanceranalysis also showed that copy number alteration of the IFN gene cluster is significantly associated with decreasedoverall survival.For instance, the overall survival of patients with braingliomareduced from 93 months (diploidy) to 24 months. In conclusion, the copy number alteration of the IFN gene cluster is associated with increasedmortalityand decreasedoverall survivalin cancer.[1]
Use of Interferon type I in therapeutics
[edit]In cancer
[edit]From the 1980s onward, members of type-I IFN family have been the standard care as immunotherapeutic agents in cancer therapy. In particular, IFNα has been approved by theUS Food and Drug Administration(FDA) for cancer. To date, pharmaceutical companies produce several types of recombinant andpegylatedIFNα for clinical use; e.g., IFNα2a (Roferon-A,Roche), IFNα2b (Intron-A,Schering-Plough) and pegylated IFNα2b (Sylatron, Schering Corporation) for treatment ofhairy cell leukemia,melanoma,renal cell carcinoma,Kaposi's sarcoma,multiple myeloma,follicular and non-Hodgkin lymphoma, andchronic myelogenous leukemia.Human IFNβ (Feron,Toray ltd.) has also been approved in Japan to treatglioblastoma,medulloblastoma,astrocytoma,andmelanoma.[1]
Combinational therapy withPD-1/PD-L1 inhibitors
[edit]By combiningPD-1/PD-L1 inhibitorswith type I interferons, researchers aim to tackle multiple resistance mechanisms and enhance the overall anti-tumor immune response. The approach is supported by preclinical and clinical studies that show promising synergistic effects, particularly inmelanomaandrenal carcinoma.These studies reveal increased infiltration andactivation of T cellswithin thetumor microenvironment,the development ofmemory T cells,and prolonged patient survival.[12]
In viral infection
[edit]Due to their strong antiviral properties, recombinant type 1 IFNs can be used for the treatment for persistent viral infection. Pegylated IFN-α is the current standard of care when it comes to chronic Hepatitis B and C infection.[13]
In multiple sclerosis
[edit]Currently, there are four FDA approved variants of IFN-β1 used as a treatment for relapsingmultiple sclerosis.[14]IFN-β1 is not an appropriate treatment for patients with progressive, non-relapsing forms of multiple sclerosis.[15]Whilst the mechanism of action is not completely understood, the use of IFN-β1 has been found to reduce brain lesions, increase the expression of anti-inflammatory cytokines and reduce T cell infiltration into the brain.[16][17]
Side effects of type I interferon therapy
[edit]One of the major limiting factors in the efficacy of type I interferon therapy are the high rates of side effects. Between 15% - 40% of people undergoing type 1 IFN treatment develop major depressive disorders.[18]Less commonly, interferon treatment has also been associated with anxiety, lethargy, psychosis and parkinsonism.[19]Mood disorders associated with IFN therapy can be reversed by discontinuation of treatment, and IFN therapy related depression is effectively treated with the selective serotonin reuptake inhibitor class of antidepressants.[20]
Interferonopathies
[edit]Interferonopathies are a class of hereditary auto-inflammatory and autoimmune diseases characterised by upregulated type 1 interferon and downstream interferon stimulated genes. The symptoms of these diseases fall in a wide clinical spectrum, and often resemble those of viral infections acquired while the child is in utero, although lacking any infectious origin.[21]The aetiology is largely still unknown, but the most common genetic mutations are associated with nucleic acid regulation, leading most researchers to suggest these arise from the failure of antiviral systems to differentiate between host and viral DNA and RNA.[22]
Non-mammalian types
[edit]Avian type I IFNs have been characterized and preliminarily assigned to subtypes (IFN I, IFN II, and IFN III), but their classification into subtypes should await a more extensive characterization of avian genomes.[citation needed]
Functional lizard type I IFNs can be found in lizard genome databases.[citation needed]
Turtle type I IFNs have been purified (references from 1970s needed). They resemble mammalian homologs.
The existence of amphibian type I IFNs have been inferred by the discovery of the genes encoding their receptor chains. They have not yet been purified, or their genes cloned.
Piscine (bony fish) type I IFN has been cloned first in zebrafish.[23][24]and then in many other teleost species including salmon and mandarin fish.[25][26]With few exceptions, and in stark contrast to avian and especially mammalian IFNs, they are present as single genes (multiple genes are however seen in polyploid fish genomes, possibly arising from whole-genome duplication). Unlike amniote IFN genes, piscine type I IFN genes contain introns, in similar positions as do their orthologs, certain interleukins. Despite this important difference, based on their 3-D structure these piscine IFNs have been assigned as Type I IFNs.[27]While in mammalian species all Type I IFNs bind to a single receptor complex, the different groups of piscine type I IFNs bind to different receptor complexes.[28]Until now several type I IFNs (IFNa, b, c, d, e, f and h) has been identified in teleost fish with as low as only one subtype in green pufferfish and as many as six subtypes in salmon with an addition of recently identified novel subtype, IFNh in mandarin fish.[25][26]
References
[edit]- ^abcRazaghi A, Brusselaers N, Björnstedt M, Durand-Dubief M (September 2021)."Copy number alteration of the interferon gene cluster in cancer: Individual patient data meta-analysis prospects to personalized immunotherapy".Neoplasia.23(10): 1059–1068.doi:10.1016/j.neo.2021.08.004.PMC8458777.PMID34555656.
- ^Schultz U, Kaspers B, Staeheli P (May 2004). "The interferon system of non-mammalian vertebrates".Developmental and Comparative Immunology.28(5): 499–508.doi:10.1016/j.dci.2003.09.009.PMID15062646.
- ^Samarajiwa SA, Wilson W, Hertzog PJ (2006). "Type I interferons: genetics and structure". In Meager A (ed.).The interferons: characterization and application.Weinheim: Wiley-VCH. pp. 3–34.ISBN978-3-527-31180-4.
- ^Zhou Q, Lavorgna A, Bowman M, Hiscott J, Harhaj EW (June 2015)."Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon".The Journal of Biological Chemistry.290(23): 14729–14739.doi:10.1074/jbc.M114.633065.PMC4505538.PMID25911105.
- ^Wang YX, Xu WG, Sun XJ, Chen YZ, Liu XY, Tang H, Jiang CL (November 2004). "Fever of recombinant human interferon-alpha is mediated by opioid domain interaction with opioid receptor inducing prostaglandin E2".Journal of Neuroimmunology.156(1–2): 107–112.doi:10.1016/j.jneuroim.2004.07.013.PMID15465601.S2CID9067557.
- ^Jablonska J, Leschner S, Westphal K, Lienenklaus S, Weiss S (April 2010)."Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model".The Journal of Clinical Investigation.120(4): 1151–1164.doi:10.1172/JCI37223.PMC2846036.PMID20237412.
- "The immune system's guard against cancer".Helmholtz Centre for Infection Research.2010-04-06.
- ^Charoenthongtrakul S, Zhou Q, Shembade N, Harhaj NS, Harhaj EW (July 2011)."Human T cell leukemia virus type 1 Tax inhibits innate antiviral signaling via NF-kappaB-dependent induction of SOCS1".Journal of Virology.85(14): 6955–6962.doi:10.1128/JVI.00007-11.PMC3126571.PMID21593151.
- ^Oritani K, Tomiyama Y (November 2004). "Interferon-zeta/limitin: novel type I interferon that displays a narrow range of biological activity".International Journal of Hematology.80(4): 325–331.doi:10.1532/ijh97.04087.PMID15615256.S2CID41691122.
- ^Hardy MP, Owczarek CM, Jermiin LS, Ejdebäck M, Hertzog PJ (August 2004). "Characterization of the type I interferon locus and identification of novel genes".Genomics.84(2): 331–345.doi:10.1016/j.ygeno.2004.03.003.PMID15233997.
- ^abYang LM, Xue QH, Sun L, Zhu YP, Liu WJ (February 2007). "Cloning and characterization of a novel feline IFN-omega".Journal of Interferon & Cytokine Research.27(2): 119–127.doi:10.1089/jir.2006.0094.PMID17316139.
- ^Todd S, Naylor SL (July 1992). "New chromosomal mapping assignments for argininosuccinate synthetase pseudogene 1, interferon-beta 3 gene, and the diazepam binding inhibitor gene".Somatic Cell and Molecular Genetics.18(4): 381–385.doi:10.1007/BF01235761.PMID1440058.S2CID46694856.
- ^Razaghi, Ali; Durand-Dubief, Mickaël; Brusselaers, Nele; Björnstedt, Mikael (2023)."Combining PD-1/PD-L1 blockade with type I interferon in cancer therapy".Frontiers in Immunology.14.doi:10.3389/fimmu.2023.1249330.ISSN1664-3224.PMC10484344.PMID37691915.
- ^Foster GR. Past, present, and future hepatitis C treatments. Semin Liver Dis 2004;24:97–104. [PubMed:15346252]
- ^Filipi M, Jack S. Interferons in the Treatment of Multiple Sclerosis: A Clinical Efficacy, Safety, and Tolerability Update.Int J MS Care.2020;22(4):165-172. doi:10.7224/1537-2073.2018-063
- ^American Academy of Neurology(February 2013),"Five Things Physicians and Patients Should Question",Choosing Wisely:an initiative of theABIM Foundation,American Academy of Neurology,retrievedAugust 1,2013,which cites
- La Mantia L, Vacchi L, Di Pietrantonj C, Ebers G, Rovaris M, Fredrikson S, Filippini G (January 2012). La Mantia L (ed.). "Interferon beta for secondary progressive multiple sclerosis".The Cochrane Database of Systematic Reviews.1:CD005181.doi:10.1002/14651858.CD005181.pub3.PMID22258960.
- Rojas JI, Romano M, Ciapponi A, Patrucco L, Cristiano E (January 2010). Rojas JI (ed.). "Interferon Beta for primary progressive multiple sclerosis".The Cochrane Database of Systematic Reviews(1): CD006643.doi:10.1002/14651858.CD006643.pub3.PMID20091602.
- ^Kieseier BC. The mechanism of action of interferon-beta in relapsing multiple sclerosis. CNS Drugs. 2011;25:491-502
- ^Kasper LH, Reder AT. Immunomodulatory activity of interferon-beta. Ann Clin Transl Neurol. 2014;1:622-631.
- ^Lotrich FE. Major depression during interferon-alpha treatment: vulnerability and prevention.Dialogues Clin Neurosci.2009;11(4):417-425. doi:10.31887/DCNS.2009.11.4/felotrich
- ^Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management.CNS Drugs.2005;19(2):105-123. doi:10.2165/00023210-200519020-00002
- ^Pinto EF, Andrade C. Interferon-Related Depression: A Primer on Mechanisms, Treatment, and Prevention of a Common Clinical Problem.Curr Neuropharmacol.2016;14(7):743-748. doi:10.2174/1570159x14666160106155129
- ^d'Angelo DM, Di Filippo P, Breda L and Chiarelli F (2021) Type I Interferonopathies in Children: An Overview.Front. Pediatr.9:631329. doi: 10.3389/fped.2021.631329
- ^Crow, Yanick J.; Stetson, Daniel B. (2022)."The type I interferonopathies: 10 years on".Nature Reviews Immunology.22(8): 471–483.doi:10.1038/s41577-021-00633-9.PMC8527296.PMID34671122.
- ^Altmann SM, Mellon MT, Distel DL, Kim CH (February 2003)."Molecular and functional analysis of an interferon gene from the zebrafish, Danio rerio".Journal of Virology.77(3): 1992–2002.doi:10.1128/jvi.77.3.1992-2002.2003.PMC140984.PMID12525633.
- ^Lutfalla G, Roest Crollius H, Stange-Thomann N, Jaillon O, Mogensen K, Monneron D (July 2003)."Comparative genomic analysis reveals independent expansion of a lineage-specific gene family in vertebrates: the class II cytokine receptors and their ligands in mammals and fish".BMC Genomics.4(1): 29.doi:10.1186/1471-2164-4-29.PMC179897.PMID12869211.
- ^abLaghari ZA, Chen SN, Li L, Huang B, Gan Z, Zhou Y, et al. (July 2018)."Functional, signalling and transcriptional differences of three distinct type I IFNs in a perciform fish, the mandarin fish Siniperca chuatsi".Developmental and Comparative Immunology.84(1): 94–108.doi:10.1016/j.dci.2018.02.008.PMID29432791.S2CID3455413.Archived fromthe originalon 2020-06-17.Retrieved2019-12-12.
- ^abBoudinot P, Langevin C, Secombes CJ, Levraud JP (November 2016)."The Peculiar Characteristics of Fish Type I Interferons".Viruses.8(11): 298.doi:10.3390/v8110298.PMC5127012.PMID27827855.
- ^Hamming OJ, Lutfalla G, Levraud JP, Hartmann R (August 2011)."Crystal structure of Zebrafish interferons I and II reveals conservation of type I interferon structure in vertebrates".Journal of Virology.85(16): 8181–8187.doi:10.1128/JVI.00521-11.PMC3147990.PMID21653665.
- ^Aggad D, Mazel M, Boudinot P, Mogensen KE, Hamming OJ, Hartmann R, et al. (September 2009)."The two groups of zebrafish virus-induced interferons signal via distinct receptors with specific and shared chains".Journal of Immunology.183(6): 3924–3931.doi:10.4049/jimmunol.0901495.PMID19717522.
External links
[edit]- Interferon+Type+Iat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- "Interferon".Drug Information Portal.U.S. National Library of Medicine.