interferon type I

IFN-α and IFN-β are secreted by many cell types including lymphocytes (NK cells, B-cells and T-cells), macrophages, fibroblasts, endothelial cells, osteoblasts and others. They stimulate both macrophages and NK cells to elicit an anti-viral response, involving IRF3/IRF7 antiviral pathways,{{cite journal | vauthors = Zhou Q, Lavorgna A, Bowman M, Hiscott J, Harhaj EW | title = Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon | journal = The Journal of Biological Chemistry | volume = 290 | issue = 23 | pages = 14729–14739 | date = June 2015 | pmid = 25911105 | pmc = 4505538 | doi = 10.1074/jbc.M114.633065 | doi-access = free }} and are also active against tumors. Plasmacytoid dendritic cells have 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|date=January 2023}}

IFN-ω is released by leukocytes at the site of viral infection or tumors.{{citation needed|date=January 2023}}

IFN-α acts as a pyrogenic factor by altering the activity of thermosensitive neurons in the hypothalamus thus causing fever. It does this by binding to opioid receptors and eliciting the release of prostaglandin-E₂ (PGE₂).{{citation needed|date=January 2023}}

A similar mechanism is used by IFN-α to reduce pain; IFN-α interacts with the μ-opioid receptor to act as an analgesic.{{cite journal | vauthors = Wang YX, Xu WG, Sun XJ, Chen YZ, Liu XY, Tang H, Jiang CL | title = Fever of recombinant human interferon-alpha is mediated by opioid domain interaction with opioid receptor inducing prostaglandin E2 | journal = Journal of Neuroimmunology | volume = 156 | issue = 1–2 | pages = 107–112 | date = November 2004 | pmid = 15465601 | doi = 10.1016/j.jneuroim.2004.07.013 | s2cid = 9067557 }}

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 blocking tumor angiogenesis and hindering the tumour from connecting into the blood vessel system.{{cite journal | vauthors = Jablonska J, Leschner S, Westphal K, Lienenklaus S, Weiss S | title = Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model | journal = The Journal of Clinical Investigation | volume = 120 | issue = 4 | pages = 1151–1164 | date = April 2010 | pmid = 20237412 | pmc = 2846036 | doi = 10.1172/JCI37223}}

• {{cite web |date=2010-04-06 |title=The immune system's guard against cancer |website=Helmholtz Centre for Infection Research |url=http://www.helmholtz-hzi.de/en/news_events/news/view/article/complete/the_immune_systems_guard_against_cancer/}}

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 and Aryl Hydrocarbon Receptor Interacting Protein (AIP).{{cite journal | vauthors = Charoenthongtrakul S, Zhou Q, Shembade N, Harhaj NS, Harhaj EW | title = Human T cell leukemia virus type 1 Tax inhibits innate antiviral signaling via NF-kappaB-dependent induction of SOCS1 | journal = Journal of Virology | volume = 85 | issue = 14 | pages = 6955–6962 | date = July 2011 | pmid = 21593151 | pmc = 3126571 | doi = 10.1128/JVI.00007-11 }}

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).{{cite journal | vauthors = Oritani K, Tomiyama Y | title = Interferon-zeta/limitin: novel type I interferon that displays a narrow range of biological activity | journal = International Journal of Hematology | volume = 80 | issue = 4 | pages = 325–331 | date = November 2004 | pmid = 15615256 | doi = 10.1532/ijh97.04087 | s2cid = 41691122 }}{{cite journal | vauthors = Hardy MP, Owczarek CM, Jermiin LS, Ejdebäck M, Hertzog PJ | title = Characterization of the type I interferon locus and identification of novel genes | journal = Genomics | volume = 84 | issue = 2 | pages = 331–345 | date = August 2004 | pmid = 15233997 | doi = 10.1016/j.ygeno.2004.03.003 }} Of these types, IFN-α, IFN

-ω, and IFN-τ can work across species.

The IFN-α proteins are produced mainly by plasmacytoid 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 called IFNA1, 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 as medication in hairy cell leukemia. The International Nonproprietary Name (INN) for the product is interferon alfa. The recombinant type is interferon alfacon-1. The pegylated types are pegylated interferon alfa-2a and pegylated interferon alfa-2b.

Recombinant feline interferon omega is a form of cat IFN-α (not ω) for veterinary use.{{cite journal | vauthors = Yang LM, Xue QH, Sun L, Zhu YP, Liu WJ | title = Cloning and characterization of a novel feline IFN-omega | journal = Journal of Interferon & Cytokine Research | volume = 27 | issue = 2 | pages = 119–127 | date = February 2007 | pmid = 17316139 | doi = 10.1089/jir.2006.0094 }}

The IFN-β proteins are produced in large quantities by fibroblasts. 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){{cite journal | vauthors = Todd S, Naylor SL | title = New chromosomal mapping assignments for argininosuccinate synthetase pseudogene 1, interferon-beta 3 gene, and the diazepam binding inhibitor gene | journal = Somatic Cell and Molecular Genetics | volume = 18 | issue = 4 | pages = 381–385 | date = July 1992 | pmid = 1440058 | doi = 10.1007/BF01235761 | s2cid = 46694856 }} (a gene designated IFN-β2 is actually IL-6).

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|date=January 2023}}.

IFN-ω, although having only one functional form described to date (IFNW1), has several pseudogenes: {{Gene|IFNWP2}}, {{Gene|IFNWP4}}, {{Gene|IFNWP5}}, {{Gene|IFNWP9}}, {{Gene|IFNWP15}}, {{Gene|IFNWP18}}, and {{Gene|IFNWP19}} in humans. Many non-primate placental mammals express multiple IFN-ω subtypes.

{{distinguish|Interferon gamma|IFN-γ}}

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|date=January 2023}}

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 the US Food and Drug Administration (FDA) for cancer. To date, pharmaceutical companies produce several types of recombinant and pegylated IFNα for clinical use; e.g., IFNα2a (Roferon-A, Roche), IFNα2b (Intron-A, Schering-Plough) and pegylated IFNα2b (Sylatron, Schering Corporation) for treatment of hairy cell leukemia, melanoma, renal cell carcinoma, Kaposi's sarcoma, multiple myeloma, follicular and non-Hodgkin lymphoma, and chronic myelogenous leukemia. Human IFNβ (Feron, Toray ltd.) has also been approved in Japan to treat glioblastoma, medulloblastoma, astrocytoma, and melanoma.[https://doi.org/10.1016/j.neo.2021.08.004]

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 24 cancer types. Notably deletion of this cluster is significantly associated with increased mortality in many cancer types particularly uterus, kidney, and brain cancers. The Cancer Genome Atlas PanCancer analysis also showed that copy number alteration of the IFN gene cluster is significantly associated with decreased overall survival. For instance, the overall survival of patients with brain glioma reduced from 93 months (diploidy) to 24 months. In conclusion, the copy number alteration of the IFN gene cluster is associated with increased mortality and decreased overall survival in cancer.

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 the US Food and Drug Administration (FDA) for cancer. To date, pharmaceutical companies produce several types of recombinant and pegylated IFNα for clinical use; e.g., IFNα2a (Roferon-A, Roche), IFNα2b (Intron-A, Schering-Plough) and pegylated IFNα2b (Sylatron, Schering Corporation) for treatment of hairy cell leukemia, melanoma, renal cell carcinoma, Kaposi's sarcoma, multiple myeloma, follicular and non-Hodgkin lymphoma, and chronic myelogenous leukemia. Human IFNβ (Feron, Toray ltd.) has also been approved in Japan to treat glioblastoma, medulloblastoma, astrocytoma, and melanoma.

By combining PD-1/PD-L1 inhibitors with 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 in melanoma and renal carcinoma. These studies reveal increased infiltration and activation of T cells within the tumor microenvironment, the development of memory T cells, and prolonged patient survival.{{Cite journal |last1=Razaghi |first1=Ali |last2=Durand-Dubief |first2=Mickaël |last3=Brusselaers |first3=Nele |last4=Björnstedt |first4=Mikael |date=2023 |title=Combining PD-1/PD-L1 blockade with type I interferon in cancer therapy |journal=Frontiers in Immunology |volume=14 |doi=10.3389/fimmu.2023.1249330 |pmid=37691915 |pmc=10484344 |issn=1664-3224|doi-access=free }}

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.Foster GR. Past, present, and future hepatitis C treatments. Semin Liver Dis 2004;24:97–104. [PubMed:15346252]

Currently, there are four FDA approved variants of IFN-β1 used as a treatment for relapsing multiple sclerosis.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 IFN-β1 is not an appropriate treatment for patients with progressive, non-relapsing forms of multiple sclerosis.{{Citation |author1=American Academy of Neurology |title=Five Things Physicians and Patients Should Question |date=February 2013 |url=http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-neurology/ |work=Choosing Wisely: an initiative of the ABIM Foundation |publisher=American Academy of Neurology |access-date=August 1, 2013 |author1-link=American Academy of Neurology}}, which cites

• {{cite journal |vauthors=La Mantia L, Vacchi L, Di Pietrantonj C, Ebers G, Rovaris M, Fredrikson S, Filippini G |date=January 2012 |title=Interferon beta for secondary progressive multiple sclerosis |journal=The Cochrane Database of Systematic Reviews |volume=1 |pages=CD005181 |doi=10.1002/14651858.CD005181.pub3 |pmid=22258960 |veditors=La Mantia L|pmc=11627149 }}
• {{cite journal |vauthors=Rojas JI, Romano M, Ciapponi A, Patrucco L, Cristiano E |date=January 2010 |title=Interferon Beta for primary progressive multiple sclerosis |journal=The Cochrane Database of Systematic Reviews |issue=1 |pages=CD006643 |doi=10.1002/14651858.CD006643.pub3 |pmid=20091602 |veditors=Rojas JI}}

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.Kieseier  BC.  The  mechanism  of  action  of  interferon-beta  in  relapsing  multiple sclerosis. CNS Drugs. 2011;25:491-502Kasper  LH,  Reder  AT.  Immunomodulatory  activity  of  interferon-beta.  Ann Clin Transl Neurol. 2014;1:622-631.

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.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 Less commonly, interferon treatment has also been associated with anxiety, lethargy, psychosis and parkinsonism.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 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.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

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.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 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.{{cite journal | doi=10.1038/s41577-021-00633-9 | title=The type I interferonopathies: 10 years on | year=2022 | last1=Crow | first1=Yanick J. | last2=Stetson | first2=Daniel B. | journal=Nature Reviews Immunology | volume=22 | issue=8 | pages=471–483 | pmid=34671122 | pmc=8527296 }}

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|date=January 2023}}

Functional lizard type I IFNs can be found in lizard genome databases.{{citation needed|date=January 2023}}

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.{{cite journal | vauthors = Altmann SM, Mellon MT, Distel DL, Kim CH | title = Molecular and functional analysis of an interferon gene from the zebrafish, Danio rerio | journal = Journal of Virology | volume = 77 | issue = 3 | pages = 1992–2002 | date = February 2003 | pmid = 12525633 | pmc = 140984 | doi = 10.1128/jvi.77.3.1992-2002.2003 }}{{cite journal | vauthors = Lutfalla G, Roest Crollius H, Stange-Thomann N, Jaillon O, Mogensen K, Monneron D | title = 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 | journal = BMC Genomics | volume = 4 | issue = 1 | pages = 29 | date = July 2003 | pmid = 12869211 | pmc = 179897 | doi = 10.1186/1471-2164-4-29 | doi-access = free }} and then in many other teleost species including salmon and mandarin fish.{{cite journal | vauthors = Laghari ZA, Chen SN, Li L, Huang B, Gan Z, Zhou Y, Huo HJ, Hou J, Nie P | display-authors = 6 | title = Functional, signalling and transcriptional differences of three distinct type I IFNs in a perciform fish, the mandarin fish Siniperca chuatsi | journal = Developmental and Comparative Immunology | volume = 84 | issue = 1 | pages = 94–108 | date = July 2018 | pmid = 29432791 | doi = 10.1016/j.dci.2018.02.008 | url = http://ir.ihb.ac.cn/handle/342005/30343 | access-date = 2019-12-12 | url-status = dead | s2cid = 3455413 | archive-url = https://web.archive.org/web/20200617060824/http://ir.ihb.ac.cn/handle/342005/30343 | archive-date = 2020-06-17 }}{{cite journal | vauthors = Boudinot P, Langevin C, Secombes CJ, Levraud JP | title = The Peculiar Characteristics of Fish Type I Interferons | journal = Viruses | volume = 8 | issue = 11 | pages = 298 | date = November 2016 | pmid = 27827855 | pmc = 5127012 | doi = 10.3390/v8110298 | doi-access = free }} 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.{{cite journal | vauthors = Hamming OJ, Lutfalla G, Levraud JP, Hartmann R | title = Crystal structure of Zebrafish interferons I and II reveals conservation of type I interferon structure in vertebrates | journal = Journal of Virology | volume = 85 | issue = 16 | pages = 8181–8187 | date = August 2011 | pmid = 21653665 | pmc = 3147990 | doi = 10.1128/JVI.00521-11 }} 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.{{cite journal | vauthors = Aggad D, Mazel M, Boudinot P, Mogensen KE, Hamming OJ, Hartmann R, Kotenko S, Herbomel P, Lutfalla G, Levraud JP | display-authors = 6 | title = The two groups of zebrafish virus-induced interferons signal via distinct receptors with specific and shared chains | journal = Journal of Immunology | volume = 183 | issue = 6 | pages = 3924–3931 | date = September 2009 | pmid = 19717522 | doi = 10.4049/jimmunol.0901495 | doi-access = free }} 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.

{{reflist|35em}}

• {{MeshName|Interferon+Type+I}}
• {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/interferon | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Interferon }}

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Category:Cytokines

Category:Antiviral drugs

Category:Immunostimulants