Array ( [0] => {{short description|Signaling proteins released by host cells in response to the presence of pathogens}} [1] => {{Redirect|IFN}} [2] => {{Pfam_box [3] => | Symbol = Interferons [4] => | Name = Interferon type I (α/β/δ...) [5] => | image = 1RH2 Recombinant Human Interferon-Alpha 2b-01.png [6] => | width = [7] => | caption = The molecular structure of human interferon-alpha ({{PDB|1RH2}}) [8] => | Pfam= PF00143 [9] => | InterPro= IPR000471 [10] => | SMART= SM00076 [11] => | Prosite = PDOC00225 [12] => | SCOP = 1au1 [13] => | CATH = 1au0 [14] => | TCDB = [15] => | OPM family= [16] => | OPM protein= [17] => |CDD=cd00095 [18] => }} [19] => {{Pfam box [20] => |Name=Interferon type II (γ) [21] => |InterPro=IPR002069 [22] => |Pfam=PF00714 [23] => |Symbol=IFN-gamma [24] => |CATH=1d9cA00 [25] => |SCOP=d1d9ca_ [26] => |image=Image:1HIG Interferon-Gamma01.png [27] => |caption=The three-dimensional structure of human [[interferon gamma]] ({{PDB|1HIG}}) [28] => }} [29] => {{Pfam box [30] => |Name=Interferon type III (λ) [31] => |Pfam=PF15177 [32] => |Symbol=IL28A [33] => |InterPro=IPR029177 [34] => |CATH=3og6A00 [35] => }} [36] => [37] => '''Interferons''' ('''IFN'''s, {{IPAc-en|ˌ|ɪ|n|t|ər|ˈ|f|ɪər|ɒ|n}} {{respell|IN|tər|FEER|on}}{{Cite web | url=https://www.lexico.com/en/definition/interferon | title=Interferon {{pipe}} Definition of Interferon by Lexico | access-date=2019-10-17 | archive-date=2020-12-22 | archive-url=https://web.archive.org/web/20201222183022/https://www.lexico.com/en/definition/interferon | url-status=live }}) are a group of [[signaling protein]]s{{cite journal | vauthors = De Andrea M, Ravera R, Gioia D, Gariglio M, Landolfo S | title = The interferon system: an overview | journal = European Journal of Paediatric Neurology | volume = 6 Suppl A | issue = 6 | pages = A41–6; discussion A55–8 | date = 2002 | pmid = 12365360 | doi = 10.1053/ejpn.2002.0573 | s2cid = 4523675 }} made and released by [[host cells]] in response to the presence of several [[virus]]es. In a typical scenario, a virus-infected cell will release interferons causing nearby [[cell (biology)|cells]] to heighten their anti-viral defenses. [38] => [39] => IFNs belong to the large class of [[proteins]] known as [[cytokine]]s, molecules used for communication between cells to trigger the protective defenses of the [[immune system]] that help eradicate pathogens.{{cite journal | vauthors = Parkin J, Cohen B | title = An overview of the immune system | journal = Lancet | volume = 357 | issue = 9270 | pages = 1777–89 | date = June 2001 | pmid = 11403834 | doi = 10.1016/S0140-6736(00)04904-7 | s2cid = 165986 }} Interferons are named for their ability to "interfere" with [[viral replication]] by protecting cells from [[virus infection]]s. However, virus-encoded genetic elements have the ability to antagonize the IFN response, contributing to viral pathogenesis and viral diseases.{{Cite journal|last1=Elrefaey|first1=Ahmed M. E.|last2=Hollinghurst|first2=Philippa|last3=Reitmayer|first3=Christine M.|last4=Alphey|first4=Luke|last5=Maringer|first5=Kevin|date=November 2021|title=Innate Immune Antagonism of Mosquito-Borne Flaviviruses in Humans and Mosquitoes|journal=Viruses|language=en|volume=13|issue=11|pages=2116|doi=10.3390/v13112116|pmid=34834923|pmc=8624719|doi-access=free}} IFNs also have various other functions: they activate [[immune cells]], such as [[natural killer cell]]s and [[macrophage]]s, and they increase host defenses by up-regulating [[antigen presentation]] by virtue of increasing the expression of [[major histocompatibility complex]] (MHC) [[antigens]]. Certain symptoms of infections, such as [[fever]], [[muscle pain]] and "flu-like symptoms", are also caused by the production of IFNs and other [[cytokines]]. [40] => [41] => More than twenty distinct IFN genes and proteins have been identified in animals, including humans. They are typically divided among three classes: Type I IFN, Type II IFN, and Type III IFN. IFNs belonging to all three classes are important for fighting [[viral infections]] and for the regulation of the immune system. [42] => [43] => ==Types of interferon== [44] => Based on the type of [[Immune receptor|receptor]] through which they signal, human interferons have been classified into three major types. [45] => * [[Interferon type I]]: All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α/β receptor ([[Interferon-alpha/beta receptor|IFNAR]]) that consists of [[IFNAR1]] and [[IFNAR2]] chains.{{cite journal | vauthors = de Weerd NA, Samarajiwa SA, Hertzog PJ | title = Type I interferon receptors: biochemistry and biological functions | journal = The Journal of Biological Chemistry | volume = 282 | issue = 28 | pages = 20053–7 | date = July 2007 | pmid = 17502368 | doi = 10.1074/jbc.R700006200 | doi-access = free }} The type I interferons present in humans are [[IFN-α]], [[IFN-β]], IFN-ε, [[IFNK|IFN-κ]] and [[Interferon type I#IFN-ω|IFN-ω]].{{cite journal | vauthors = Liu YJ | title = IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors | journal = Annual Review of Immunology | volume = 23 | pages = 275–306 | date = 2005 | pmid = 15771572 | doi = 10.1146/annurev.immunol.23.021704.115633 }} Interferon beta ([[IFN-β]]) can be produced by all nucleated cells when they recognize that a virus has invaded them. The most prolific producers of IFN-α and IFN-β are [[plasmacytoid dendritic cell]]s circulating in the blood. [[Monocytes]] and [[macrophages]] can also produce large amounts of type I interferons when stimulated by viral molecular patterns. The production of type I IFN-α is inhibited by another cytokine known as Interleukin-10. Once released, type I interferons bind to the [[Interferon-alpha/beta receptor|IFN-α/β receptor]] on target cells, which leads to expression of proteins that will prevent the virus from producing and replicating its RNA and DNA.{{cite journal | vauthors = Levy DE, Marié IJ, Durbin JE | title = Induction and function of type I and III interferon in response to viral infection | journal = Current Opinion in Virology | volume = 1 | issue = 6 | pages = 476–86 | date = December 2011 | pmid = 22323926 | pmc = 3272644 | doi = 10.1016/j.coviro.2011.11.001 }} Overall, IFN-α can be used to treat hepatitis B and C infections, while IFN-β can be used to treat multiple sclerosis. [46] => * [[Interferon type II]] ([[IFN-γ]] in humans): This is also known as immune interferon and is activated by Interleukin-12. Type II interferons are also released by [[cytotoxic T cell]]s and type-1 [[T helper cell]]s. However, they block the proliferation of type-2 T helper cells. The previous results in an inhibition of [[Th2|Th2]] immune response and a further induction of [[Th1 cell|Th1]] immune response.{{cite journal|last1=Kidd|first1=P|title=Th1/Th2 Balance: the hypothesis, its limitations, and implications for health and disease|journal=Alternative Medicine Review|volume=8|issue=3|pages=223–46|pmid=12946237|year=2003}} IFN type II binds to [[IFNGR]], which consists of [[IFNGR1]] and [[IFNGR2]] chains. [47] => * [[Interferon type III]]: Signal through a receptor complex consisting of [[Interleukin 10 receptor, beta subunit|IL10R2]] (also called CRF2-4) and [[IFNLR1]] (also called CRF2-12). Although discovered more recently than type I and type II IFNs,{{cite journal | vauthors = Kalliolias GD, Ivashkiv LB | title = Overview of the biology of type I interferons | journal = Arthritis Research & Therapy | volume = 12 | issue = Suppl 1 | pages = S1 | date = 2010 | pmid = 20392288 | pmc = 2991774 | doi = 10.1186/ar2881 | doi-access = free }} recent information demonstrates the importance of Type III IFNs in some types of virus or fungal infections.Vilcek, Novel interferons, Nature Immunol. 4, 8-9. 2003{{cite journal | vauthors = Hermant P, Michiels T | title = Interferon-λ in the context of viral infections: production, response and therapeutic implications | journal = Journal of Innate Immunity | volume = 6 | issue = 5 | pages = 563–74 | date = 2014 | pmid = 24751921 | pmc = 6741612 | doi = 10.1159/000360084 }}{{cite journal | vauthors = Espinosa V, Dutta O, McElrath C, Du P, Chang YJ, Cicciarelli B, Pitler A, Whitehead I, Obar JJ, Durbin JE, Kotenko SV, Rivera A | title = Type III interferon is a critical regulator of innate antifungal immunity | journal = Science Immunology | volume = 2 | issue = 16 | pages = eaan5357 | date = October 2017 | pmid = 28986419 | pmc = 5880030 | doi = 10.1126/sciimmunol.aan5357 }} [48] => [49] => In general, type I and II interferons are responsible for regulating and activating the immune response. Expression of type I and III IFNs can be induced in virtually all cell types upon recognition of viral components, especially nucleic acids, by cytoplasmic and endosomal receptors, whereas type II interferon is induced by cytokines such as IL-12, and its expression is restricted to immune cells such as [[T cells]] and [[NK cells]].{{citation needed|date=January 2023}} [50] => [51] => == Function == [52] => All interferons share several common effects: they are antiviral agents and they modulate functions of the immune system. Administration of Type I IFN has been shown experimentally to inhibit tumor growth in animals, but the beneficial action in human tumors has not been widely documented. [53] => A virus-infected cell releases viral particles that can infect nearby cells. However, the infected cell can protect neighboring cells against a potential infection of the virus by releasing interferons. In response to interferon, cells produce large amounts of an [[enzyme]] known as [[protein kinase R]] (PKR). This enzyme [[phosphorylation|phosphorylates]] a protein known as [[eIF-2]] in response to new viral infections; the phosphorylated eIF-2 forms an inactive complex with another protein, called [[eIF2B]], to reduce protein synthesis within the cell. Another cellular enzyme, [[RNAse L]]—also induced by interferon action—destroys RNA within the cells to further reduce protein synthesis of both viral and host genes. Inhibited protein synthesis impairs both virus replication and infected host cells. In addition, interferons induce production of hundreds of other proteins—known collectively as interferon-stimulated genes (ISGs)—that have roles in combating viruses and other actions produced by interferon.{{cite journal | vauthors = Fensterl V, Sen GC | title = Interferons and viral infections | journal = BioFactors | volume = 35 | issue = 1 | pages = 14–20 | year = 2009 | pmid = 19319841 | doi = 10.1002/biof.6 | s2cid = 27209861 }}{{cite journal | vauthors = de Veer MJ, Holko M, Frevel M, Walker E, Der S, Paranjape JM, Silverman RH, Williams BR | title = Functional classification of interferon-stimulated genes identified using microarrays | journal = Journal of Leukocyte Biology | volume = 69 | issue = 6 | pages = 912–20 | date = June 2001 | doi = 10.1189/jlb.69.6.912 | pmid = 11404376 | s2cid = 1714991 | doi-access = free }} [54] => They also limit viral spread by increasing [[p53]] activity, which kills virus-infected cells by promoting [[apoptosis]].{{cite journal | vauthors = Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, Kikuchi H, Sasaki S, Imai K, Shibue T, Honda K, Taniguchi T | title = Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence | journal = Nature | volume = 424 | issue = 6948 | pages = 516–23 | date = July 2003 | pmid = 12872134 | doi = 10.1038/nature01850 | bibcode = 2003Natur.424..516T | doi-access = free }}{{cite journal | vauthors = Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G | title = DNA Damage Signaling and p53-dependent Senescence after Prolonged β-Interferon Stimulation | journal = Molecular Biology of the Cell | volume = 17 | issue = 4 | pages = 1583–92 | date = April 2006 | pmid = 16436515 | pmc = 1415317 | doi = 10.1091/mbc.E05-09-0858 }} The effect of IFN on p53 is also linked to its protective role against certain cancers. [55] => [56] => Another function of interferons is to up-regulate [[major histocompatibility complex]] molecules, [[MHC I]] and [[MHC II]], and increase [[immunoproteasome]] activity. All interferons significantly enhance the presentation of MHC I dependent antigens. [[Interferon gamma|Interferon gamma (IFN-gamma)]] also significantly stimulates the MHC II-dependent presentation of antigens. Higher MHC I expression increases presentation of viral and abnormal peptides from cancer cells to [[cytotoxic T cell]]s, while the immunoproteasome processes these peptides for loading onto the MHC I molecule, thereby increasing the recognition and killing of infected or malignant cells. Higher MHC II expression increases presentation of these peptides to [[helper T cell]]s; these cells release cytokines (such as more interferons and [[interleukins]], among others) that signal to and co-ordinate the activity of other immune cells.{{Cite journal|last1=Ikeda|first1=Hiroaki|last2=Old|first2=Lloyd J.|last3=Schreiber|first3=Robert D.|date=April 2002|title=The roles of IFN gamma in protection against tumor development and cancer immunoediting|journal=Cytokine & Growth Factor Reviews|volume=13|issue=2|pages=95–109 |pmid=11900986|doi=10.1016/s1359-6101(01)00038-7}}{{Cite journal|last1=Dunn|first1=Gavin P.|last2=Bruce|first2=Allen T.|last3=Sheehan|first3=Kathleen C. F.|last4=Shankaran|first4=Vijay|last5=Uppaluri|first5=Ravindra|last6=Bui|first6=Jack D.|last7=Diamond|first7=Mark S.|last8=Koebel|first8=Catherine M.|last9=Arthur|first9=Cora|date=July 2007|title=A critical function for type I interferons in cancer immunoediting|journal=Nature Immunology|volume=6|issue=7|pages=722–729|doi=10.1038/ni1213 |pmid=15951814|s2cid=20374688}}{{Cite journal|last1=Borden|first1=Ernest C.|last2=Sen|first2=Ganes C.|last3=Uze|first3=Gilles|last4=Silverman|first4=Robert H.|last5=Ransohoff|first5=Richard M.|last6=Foster|first6=Graham R.|last7=Stark|first7=George R.|date=December 2007|title=Interferons at age 50: past, current and future impact on biomedicine|journal=Nature Reviews. Drug Discovery|volume=6|issue=12|pages=975–990|doi=10.1038/nrd2422 |pmid=18049472|pmc=7097588}} [57] => [58] => Interferons can also suppress [[angiogenesis]] by down regulation of [[Angiogenesis|angiogenic]] stimuli deriving from tumor cells. They also suppress the proliferation of [[Endothelium|endothelial]] cells. Such suppression causes a decrease in tumor angiogenesis, a decrease in its [[Angiogenesis|vascularization]] and subsequent growth inhibition. Interferons, such as [[interferon gamma]], directly activate other immune cells, such as [[macrophage]]s and [[natural killer cell]]s. [59] => [60] => ==Induction of interferons== [61] => Production of interferons occurs mainly in response to microbes, such as viruses and bacteria, and their products. Binding of molecules uniquely found in microbes—viral [[glycoprotein]]s, viral [[RNA]], bacterial [[endotoxin]] (lipopolysaccharide), bacterial [[flagella]], [[CpG ODN|CpG motifs]]—by [[pattern recognition receptor]]s, such as membrane bound [[toll like receptor]]s or the cytoplasmic receptors [[DDX58|RIG-I]] or [[IFIH1|MDA5]], can trigger release of IFNs. [62] => Toll Like Receptor 3 ([[TLR 3|TLR3]]) is important for inducing interferons in response to the presence of [[double-stranded RNA viruses]]; the [[ligand]] for this receptor is [[DsRNA|double-stranded RNA (dsRNA)]]. After binding dsRNA, this receptor activates the transcription factors [[IRF3]] and [[NF-κB]], which are important for initiating synthesis of many inflammatory proteins. [[RNA interference]] technology tools such as siRNA or vector-based reagents can either silence or stimulate interferon pathways.{{cite journal | vauthors = Whitehead KA, Dahlman JE, Langer RS, Anderson DG | title = Silencing or stimulation? siRNA delivery and the immune system | journal = Annual Review of Chemical and Biomolecular Engineering | volume = 2 | pages = 77–96 | year = 2011 | pmid = 22432611 | doi = 10.1146/annurev-chembioeng-061010-114133 | s2cid = 28803811 }} Release of IFN from cells (specifically IFN-γ in lymphoid cells) is also induced by [[mitogen]]s. Other cytokines, such as [[interleukin 1]], [[interleukin 2]], [[interleukin-12]], [[Tumor necrosis factor-alpha|tumor necrosis factor]] and [[colony-stimulating factor]], can also enhance interferon production.{{cite journal | vauthors = Haller O, Kochs G, Weber F | title = Interferon, Mx, and viral countermeasures | journal = Cytokine & Growth Factor Reviews | volume = 18 | issue = 5–6 | pages = 425–33 | date = October–December 2007 | pmid = 17683972 | doi = 10.1016/j.cytogfr.2007.06.001 | pmc = 7185553 }} [63] => [64] => ==Downstream signaling== [65] => By interacting with their specific receptors, IFNs activate ''signal transducer and activator of transcription'' ([[STAT protein|STAT]]) complexes; STATs are a family of [[transcription factor]]s that regulate the expression of certain immune system genes. Some STATs are activated by both type I and type II IFNs. However each IFN type can also activate unique STATs.{{cite journal | vauthors = Platanias LC | title = Mechanisms of type-I- and type-II-interferon-mediated signalling | journal = Nature Reviews. Immunology | volume = 5 | issue = 5 | pages = 375–86 | date = May 2005 | pmid = 15864272 | doi = 10.1038/nri1604 | s2cid = 1472195 | doi-access = free }} [66] => [67] => STAT activation initiates the most well-defined cell signaling pathway for all IFNs, the classical [[Janus kinase]]-STAT ([[JAK-STAT]]) signaling pathway. In this pathway, JAKs associate with IFN receptors and, following receptor engagement with IFN, [[phosphorylation|phosphorylate]] both [[STAT1]] and [[STAT2]]. As a result, an IFN-stimulated gene factor 3 (ISGF3) complex forms—this contains STAT1, STAT2 and a third transcription factor called [[ISGF3G|IRF9]]—and moves into the [[cell nucleus]]. Inside the nucleus, the ISGF3 complex binds to specific [[nucleotide]] sequences called ''IFN-stimulated response elements'' (ISREs) in the [[promoter (biology)|promoter]]s of certain [[gene]]s, known as IFN stimulated genes [[ISGs]]. Binding of ISGF3 and other transcriptional complexes activated by IFN signaling to these specific regulatory elements induces transcription of those genes. A collection of known ISGs is available on [[Interferome]], a curated online database of ISGs ([https://web.archive.org/web/20131011000719/http://www.interferome.org/ www.interferome.org]);{{cite journal | vauthors = Samarajiwa SA, Forster S, Auchettl K, Hertzog PJ | title = INTERFEROME: the database of interferon regulated genes | journal = Nucleic Acids Research | volume = 37 | issue = Database issue | pages = D852-7 | date = January 2009 | pmid = 18996892 | pmc = 2686605 | doi = 10.1093/nar/gkn732 }} Additionally, STAT homodimers or heterodimers form from different combinations of STAT-1, -3, -4, -5, or -6 during IFN signaling; these [[protein dimer|dimer]]s initiate gene transcription by binding to IFN-activated site (GAS) elements in gene promoters. Type I IFNs can induce expression of genes with either ISRE or GAS elements, but gene induction by type II IFN can occur only in the presence of a GAS element. [68] => [69] => In addition to the JAK-STAT pathway, IFNs can activate several other signaling cascades. For instance, both type I and type II IFNs activate a member of the CRK family of [[Signal transducing adaptor protein|adaptor protein]]s called [[CRKL]], a nuclear adaptor for [[STAT5]] that also regulates signaling through the [[RAPGEF1|C3G]]/[[Rap1]] pathway. Type I IFNs further activate ''[[p38 mitogen-activated protein kinase]]'' (MAP kinase) to induce gene transcription. Antiviral and antiproliferative effects specific to type I IFNs result from p38 MAP kinase signaling. The ''[[phosphatidylinositol 3-kinase]]'' (PI3K) signaling pathway is also regulated by both type I and type II IFNs. PI3K activates [[P70-S6 Kinase 1]], an enzyme that increases protein synthesis and cell proliferation; phosphorylates [[ribosomal protein s6]], which is involved in protein synthesis; and phosphorylates a translational repressor protein called ''eukaryotic translation-initiation factor 4E-binding protein 1'' ([[EIF4EBP1]]) in order to deactivate it. [70] => [71] => Interferons can disrupt signaling by other stimuli. For example, interferon alpha induces RIG-G, which disrupts the CSN5-containing COP9 signalosome (CSN), a highly conserved multiprotein complex implicated in protein deneddylation, deubiquitination, and phosphorylation.{{cite journal | vauthors = Xu GP, Zhang ZL, Xiao S, Zhuang LK, Xia D, Zou QP, Jia PM, Tong JH | title = Rig-G negatively regulates SCF-E3 ligase activities by disrupting the assembly of COP9 signalosome complex | journal = Biochemical and Biophysical Research Communications | volume = 432 | issue = 3 | pages = 425–30 | date = March 2013 | pmid = 23415865 | doi = 10.1016/j.bbrc.2013.01.132 }} RIG-G has shown the capacity to inhibit NF-κB and STAT3 signaling in lung cancer cells, which demonstrates the potential of type I IFNs.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} [72] => [73] => ==Viral resistance to interferons== [74] => Many viruses have evolved mechanisms to resist interferon activity.{{cite journal | vauthors = Navratil V, de Chassey B, Meyniel L, Pradezynski F, André P, Rabourdin-Combe C, Lotteau V | title = System-level comparison of protein-protein interactions between viruses and the human type I interferon system network | journal = Journal of Proteome Research | volume = 9 | issue = 7 | pages = 3527–36 | date = July 2010 | pmid = 20459142 | doi = 10.1021/pr100326j }} They circumvent the IFN response by blocking downstream signaling events that occur after the cytokine binds to its receptor, by preventing further IFN production, and by inhibiting the functions of proteins that are induced by IFN.{{cite journal | vauthors = Lin RJ, Liao CL, Lin E, Lin YL | title = Blocking of the alpha interferon-induced JAK-STAT signaling pathway by Japanese encephalitis virus infection | journal = Journal of Virology | volume = 78 | issue = 17 | pages = 9285–94 | date = September 2004 | pmid = 15308723 | pmc = 506928 | doi = 10.1128/JVI.78.17.9285-9294.2004 }} Viruses that inhibit IFN signaling include [[Japanese Encephalitis]] Virus (JEV), [[Dengue virus|dengue type 2 virus]] (DEN-2), and viruses of the herpesvirus family, such as human [[cytomegalovirus]] (HCMV) and [[Kaposi's sarcoma-associated herpesvirus]] (KSHV or HHV8).{{cite journal | vauthors = Sen GC | title = Viruses and interferons | journal = Annual Review of Microbiology | volume = 55 | pages = 255–81 | year = 2001 | pmid = 11544356 | doi = 10.1146/annurev.micro.55.1.255 }} Viral proteins proven to affect IFN signaling include [[EBV nuclear antigen 1|EBV nuclear antigen 1 (EBNA1)]] and [[EBV nuclear antigen 2|EBV nuclear antigen 2 (EBNA-2)]] from [[Epstein-Barr virus]], the [[large T antigen]] of [[Polyomavirus]], the E7 protein of [[Human papillomavirus]] (HPV), and the B18R protein of [[vaccinia virus]].{{cite journal | vauthors = Alcamí A, Symons JA, Smith GL | title = The vaccinia virus soluble alpha/beta interferon (IFN) receptor binds to the cell surface and protects cells from the antiviral effects of IFN | journal = Journal of Virology | volume = 74 | issue = 23 | pages = 11230–9 | date = December 2000 | pmid = 11070021 | pmc = 113220 | doi = 10.1128/JVI.74.23.11230-11239.2000 }} Reducing IFN-α activity may prevent signaling via [[STAT1]], [[STAT2]], or [[ISGF3G|IRF9]] (as with JEV infection) or through the [[JAK-STAT]] pathway (as with DEN-2 infection). Several [[poxvirus]]es encode soluble IFN receptor homologs—like the B18R protein of the vaccinia virus—that bind to and prevent IFN interacting with its cellular receptor, impeding communication between this cytokine and its target cells. Some viruses can encode proteins that bind to [[double-stranded RNA]] (dsRNA) to prevent the activity of RNA-dependent [[protein kinase]]s; this is the mechanism [[reovirus]] adopts using its sigma 3 (σ3) protein, and vaccinia virus employs using the gene product of its E3L gene, p25.{{cite journal | vauthors = Minks MA, West DK, Benvin S, Baglioni C | title = Structural requirements of double-stranded RNA for the activation of 2',5'-oligo(A) polymerase and protein kinase of interferon-treated HeLa cells | journal = The Journal of Biological Chemistry | volume = 254 | issue = 20 | pages = 10180–3 | date = October 1979 | doi = 10.1016/S0021-9258(19)86690-5 | pmid = 489592 | doi-access = free }}{{cite journal | vauthors = Miller JE, Samuel CE | title = Proteolytic cleavage of the reovirus sigma 3 protein results in enhanced double-stranded RNA-binding activity: identification of a repeated basic amino acid motif within the C-terminal binding region | journal = Journal of Virology | volume = 66 | issue = 9 | pages = 5347–56 | date = September 1992 | pmid = 1501278 | pmc = 289090 | doi = 10.1128/JVI.66.9.5347-5356.1992}}{{cite journal | vauthors = Chang HW, Watson JC, Jacobs BL | title = The E3L gene of vaccinia virus encodes an inhibitor of the interferon-induced, double-stranded RNA-dependent protein kinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 11 | pages = 4825–9 | date = June 1992 | pmid = 1350676 | pmc = 49180 | doi = 10.1073/pnas.89.11.4825 | bibcode = 1992PNAS...89.4825C | doi-access = free }} The ability of interferon to induce protein production from interferon stimulated genes (ISGs) can also be affected. Production of [[protein kinase R]], for example, can be disrupted in cells infected with JEV. Some viruses escape the anti-viral activities of interferons by gene (and thus protein) mutation. The [[H5N1]] [[influenza]] virus, also known as bird flu, has resistance to interferon and other anti-viral cytokines that is attributed to a single [[amino acid]] change in its Non-Structural Protein 1 (NS1), although the precise mechanism of how this confers immunity is unclear.{{cite journal | vauthors = Seo SH, Hoffmann E, Webster RG | title = Lethal H5N1 influenza viruses escape host anti-viral cytokine responses | journal = Nature Medicine | volume = 8 | issue = 9 | pages = 950–4 | date = September 2002 | pmid = 12195436 | doi = 10.1038/nm757 | s2cid = 8293109 }} The relative resistance of [[hepatitis C virus]] genotype I to interferon-based therapy has been attributed in part to homology between viral envelope protein E2 and host protein kinase R, a mediator of interferon-induced suppression of viral protein translation,{{cite journal|vauthors=Taylor DR, Shi ST, Romano PR, Barber GN, Lai MM|journal=Science|year=1999|volume=285|issue=5424|pages=107–110|doi=10.1126/science.285.5424.107|pmid=10390359|title=Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein}}{{cite journal|vauthors=Taylor DR, Tian B, Romano PR, Hinnebusch AG, Lai MM, Mathews MB|title=Hepatitis C Virus Envelope Protein E2 Does Not Inhibit PKR by Simple Competition with Autophosphorylation Sites in the RNA-Binding Domain|journal=Journal of Virology|volume=75|issue=3|pages=1265–1273|doi=10.1128/JVI.75.3.1265-1273.2001|doi-access=free|year=2001|pmid=11152499|pmc=114032}} although mechanisms of acquired and intrinsic resistance to interferon therapy in HCV are polyfactorial.{{cite journal|vauthors=Abid K, Quadri R, Negro F|title=Hepatitis C Virus, the E2 Envelope Protein, and α-Interferon Resistance|journal=Science|year=2000|volume=287|issue=5458|page=1555|doi=10.1126/science.287.5458.1555a|pmid=10733410|url=https://serval.unil.ch/notice/serval:BIB_3D029EC8CDF4 |doi-access=free}}{{cite journal|last=Pawlotsky|first=Jean-Michel|title=The nature of interferon-alpha resistance in hepatitis C virus infection|volume=16|issue=6|journal=Current Opinion in Infectious Diseases|pages=587–592|doi=10.1097/00001432-200312000-00012|year=2003|pmid=14624110|s2cid=72191620 }} [75] => [76] => ==Coronavirus response== [77] => [[Coronavirus]]es evade [[Innate immune system|innate immunity]] during the first ten days of viral infection.{{cite journal | vauthors = Sa Ribero M, Jouvenet N, Dreux M, Sébastien Nisole S | title = Interplay between SARS-CoV-2 and the type I interferon response | journal = [[PLOS Pathogens]] | volume = 16 | issue=7 | pages = e1008737 | date = 2020 | doi = 10.1371/journal.ppat.1008737 | pmc = 7390284 | pmid = 32726355 | doi-access = free }} In the early stages of infection, [[Severe acute respiratory syndrome coronavirus 2|SARS-CoV-2]] induces an even lower [[interferon type I]] (IFN-I) response than [[Severe acute respiratory syndrome coronavirus 1|SARS-CoV]], which itself is a weak IFN-I inducer in human cells.{{cite journal | vauthors = Palermo E, Di Carlo D, Sgarbanti M, Hiscott J | title = Type I Interferons in COVID-19 Pathogenesis | journal = [[Biology (journal)|Biology]] | volume = 10 | issue=9 | date = 2021 | page = 829 | doi = 10.3390/biology10090829 | pmc = 8468334 | pmid = 34571706| doi-access = free }} SARS-CoV-2 limits the IFN-III response as well.{{cite journal | vauthors = Toor SM, Saleh R, Elkord E | title = T-cell responses and therapies against SARS-CoV-2 infection | journal = [[Immunology (journal)|Immunology]] | volume = 162 | issue=1| pages = 30–43 | date = 2021 | doi = 10.1111/imm.13262 | pmc = 7730020 | pmid = 32935333}} Reduced numbers of [[plasmacytoid dendritic cell]]s with age is associated with increased [[COVID-19]] severity, possibly because these cells are substantial interferon producers.{{cite journal | vauthors=Bartleson JM, Radenkovic D, Verdin E | title=SARS-CoV-2, COVID-19 and the Ageing Immune System | journal=[[List of Nature Research journals#N|Nature Aging]] | volume=1 | issue=9 | pages=769–782 | year=2021 | doi = 10.1038/s43587-021-00114-7 | pmc=8570568 | pmid=34746804 }} [78] => [79] => Ten percent of patients with life-threatening COVID-19 have [[Autoantibody|autoantibodies]] against type I interferon. [80] => [81] => Delayed IFN-I response contributes to the pathogenic inflammation ([[cytokine storm]]) seen in later stages of [[COVID-19]] disease.{{cite journal | vauthors = Park A, Iwasaki A | title = Type I and Type III Interferons - Induction, Signaling, Evasion, and Application to Combat COVID-19 | journal = [[Cell Host & Microbe]] | volume = 27 | issue=6 | pages = 870–878 | date = 2020 | doi = 10.1016/j.chom.2020.05.008 | pmc = 7255347 | pmid = 32464097}} Application of IFN-I prior to (or in the very early stages of) viral infection can be protective, as can treatment with pegylated IFN-λIII,{{cite journal|vauthors=Reis G, Moreira Silva EA, Medeiros Silva DC, Thabane L, Campos VH, Ferreira TS, Santos CV, Nogueira AM, Almeida AP, Savassi LC, Figueiredo-Neto AD, Dias AC, Freire Júnior AM, Bitarães C, Milagres AC, Callegari ED, Simplicio MI, Ribeiro LB, Oliveira R, Harari O, Wilson LA, Forrest JI, Ruton H, Sprague S, McKay P, Guo CM, Limbrick-Oldfield EH, Kanters S, Guyatt GH, Rayner CR, Kandel C, Biondi MJ, Kozak R, Hansen B, Zahoor MA, Arora P, Hislop C, Choong I, Feld JJ, Mills EJ, Glenn JS, ((TOGETHER Investigators))|display-authors=6|title=Early Treatment with Pegylated Interferon Lambda for COVID-19|journal=New England Journal of Medicine|volume=388|issue=6|year=2023|pages=518–528|doi=10.1056/NEJMoa2209760|pmid=36780676|pmc=9933926}} which should be validated in randomized clinical trials. [82] => [83] => ==Interferon therapy== [84] => [[Image:Vials of Interferon Image 3549-PH.jpg|thumb|right|200px|Three vials filled with human leukocyte interferon]] [85] => [86] => ===Diseases=== [87] => [88] => [[Interferon beta-1a]] and [[interferon beta-1b]] are used to treat and control [[multiple sclerosis]], an [[autoimmune disorder]]. This treatment may help in reducing attacks in relapsing-remitting multiple sclerosis{{Cite journal|last1=Rice|first1=G. P.|last2=Incorvaia|first2=B.|last3=Munari|first3=L.|last4=Ebers|first4=G.|last5=Polman|first5=C.|last6=D'Amico|first6=R.|last7=Filippini|first7=G.|date=2001|title=Interferon in relapsing-remitting multiple sclerosis|journal=The Cochrane Database of Systematic Reviews|volume=2001 |issue=4|pages=CD002002|doi=10.1002/14651858.CD002002 |pmc=7017973|pmid=11687131}} and slowing disease progression and activity in secondary progressive multiple sclerosis.{{cite journal | vauthors = Paolicelli D, Direnzo V, Trojano M | title = Review of interferon beta-1b in the treatment of early and relapsing multiple sclerosis | journal = Biologics: Targets and Therapy | volume = 3 | pages = 369–76 | date = 14 September 2009 | pmid = 19707422 | pmc = 2726074 }} [89] => [90] => Interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for some cancers.{{cite journal | vauthors = Goldstein D, Laszlo J | title = The role of interferon in cancer therapy: a current perspective | journal = CA: A Cancer Journal for Clinicians | volume = 38 | issue = 5 | pages = 258–77 | date = Sep 1988 | pmid = 2458171 | doi = 10.3322/canjclin.38.5.258 | s2cid = 9160289 | doi-access = }} This treatment can be used in [[hematological malignancy]], such as in leukemia and lymphomas including [[hairy cell leukemia]], [[chronic myeloid leukemia]], nodular lymphoma, and [[cutaneous T-cell lymphoma]]. Patients with recurrent [[melanoma]]s receive recombinant IFN-α2b.{{cite journal | vauthors = Hauschild A, Gogas H, Tarhini A, Middleton MR, Testori A, Dréno B, Kirkwood JM | title = Practical guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant treatment for melanoma: expert opinion | journal = Cancer | volume = 112 | issue = 5 | pages = 982–94 | date = March 2008 | pmid = 18236459 | doi = 10.1002/cncr.23251 | doi-access = free }} [91] => [92] => Both [[hepatitis B]] and [[hepatitis C]] can be treated with IFN-α, often in combination with other antiviral drugs.{{cite journal | vauthors = Cooksley WG | title = The role of interferon therapy in hepatitis B | journal = MedGenMed | volume = 6 | issue = 1 | pages = 16 | date = March 2004 | pmid = 15208528 | pmc = 1140699 }}{{cite journal | vauthors = Shepherd J, Waugh N, Hewitson P | title = Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review | journal = Health Technology Assessment | volume = 4 | issue = 33 | pages = 1–67 | year = 2000 | pmid = 11134916 | doi = 10.3310/hta4330 | doi-access = free }} Some of those treated with interferon have a sustained virological response and can eliminate hepatitis virus in the case of hepatitis C. The most common strain of hepatitis C virus (HCV) worldwide—genotype I—{{cite web |url=http://hepctrust.org.uk/information/about-hepatitis-c-virus/genotypes-hepatitis-c|title=Genotypes of hepatitis C|website=Hepatitis C Trust|year=2023|access-date=8 February 2023}} can be treated with interferon-α, ribavirin and protease inhibitors such as [[telaprevir]],{{cite journal|last=Cunningham|first=Morven|title=Efficacy and safety of telaprevir in patients with genotype 1 hepatitis C infection|journal=Therapeutic Advances in Gastroenterology|volume=5|issue=2|year=2012|pages=139–151|doi=10.1177/1756283X11426895|doi-access=free|pmid=22423262|pmc=3296085}} [[boceprevir]]{{cite journal|vauthors=Poordad F, McCone Jr J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Rajender Reddy K, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP, ((SPRINT-2 Investigators))|display-authors=6|journal=New England Journal of Medicine|volume=364|issue=13|pages=1195–1206|year=2011|doi=10.1056/NEJMoa1010494|pmid=21449783|pmc=3766849|title=Boceprevir for Untreated Chronic HCV Genotype 1 Infection}}{{cite journal|vauthors=Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R, ((HCV RESPOND-2 Investigators))|display-authors=6|journal=New England Journal of Medicine|volume=364|issue=13|pages=1207–1217|year=2011|doi=10.1056/NEJMoa1009482|pmid=21449784|pmc=3153125|title=Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection}} or the nucleotide analog polymerase inhibitor [[sofosbuvir]].{{cite journal|vauthors=Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, Schultz M, Davis MN, Kayali Z, Rajender Reddy K, Jacobson IM, Kowdley KV, Nyberg L, Mani Subramanian G, Hyland RH, Arterburn S, Jiang D, McNally J, Brainard D, Symonds WT, McHutchinson JG, Sheikh AM, Younossi Z, Gane EJ|display-authors=6|title=Sofosbuvir for previously untreated chronic hepatitis C infection|journal=New England Journal of Medicine|volume=368|issue=20|pages=1878–1887|doi=10.1056/NEJMoa1214853|pmid=23607594|doi-access=free|year=2013}} [[Biopsies]] of patients given the treatment show reductions in liver damage and [[cirrhosis]]. Control of chronic hepatitis C by IFN is associated with reduced [[hepatocellular carcinoma]].{{cite journal | vauthors = Ishikawa T | title = Secondary prevention of recurrence by interferon therapy after ablation therapy for hepatocellular carcinoma in chronic hepatitis C patients | journal = World Journal of Gastroenterology | volume = 14 | issue = 40 | pages = 6140–4 | date = October 2008 | pmid = 18985803 | pmc = 2761574 | doi = 10.3748/wjg.14.6140 | doi-access = free }} A [[single nucleotide polymorphism]] (SNP) in the gene encoding the type III interferon IFN-λ3 was found to be protective against chronic infection following proven HCV infection{{cite journal|vauthors=Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'hUigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchinson JG, Goldstein DB, Carrington M|display-authors=6|title=Genetic variation in ''IL28B'' and spontaneous clearance of hepatitis C virus|journal=Nature|year=2009|volume=461|issue=7265|pages=798–801|doi=10.1038/nature08463|pmid=19759533|pmc=3172006|bibcode=2009Natur.461..798T}} and predicted treatment response to interferon-based regimens. The frequency of the SNP differed significantly by race, partly explaining observed differences in response to interferon therapy between European-Americans and African-Americans.{{cite journal | vauthors = Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB | title = Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance | journal = Nature | volume = 461 | issue = 7262 | pages = 399–401 | date = September 2009 | pmid = 19684573 | doi = 10.1038/nature08309 | last13 = Goldstein | first12 = JG | first13 = DB | last12 = Mchutchison | bibcode = 2009Natur.461..399G | s2cid = 1707096 }} [93] => [94] => Unconfirmed results suggested that interferon eye drops may be an effective treatment for people who have [[herpes of the eye|herpes simplex virus epithelial keratitis]], a type of eye infection.{{cite journal | vauthors = Wilhelmus KR | title = Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD002898 | date = January 2015 | issue = 1 | pmid = 25879115 | pmc = 4443501 | doi = 10.1002/14651858.CD002898.pub5 }} There is no clear evidence to suggest that removing the infected tissue ([[debridement]]) followed by interferon drops is an effective treatment approach for these types of eye infections. Unconfirmed results suggested that the combination of interferon and an antiviral agent may speed the healing process compared to antiviral therapy alone. [95] => [96] => When used in systemic therapy, IFNs are mostly administered by an intramuscular injection. The injection of IFNs in the muscle or under the skin is generally well tolerated. The most frequent [[adverse effects]] are flu-like symptoms: increased body temperature, feeling ill, fatigue, headache, muscle pain, convulsion, dizziness, hair thinning, and depression. [[Erythema]], pain, and hardness at the site of injection are also frequently observed. IFN therapy causes [[immunosuppression]], in particular through [[neutropenia]] and can result in some infections manifesting in unusual ways.{{cite journal | vauthors = Bhatti Z, Berenson CS | title = Adult systemic cat scratch disease associated with therapy for hepatitis C | journal = BMC Infectious Diseases | volume = 7 | pages = 8 | date = February 2007 | pmid = 17319959 | pmc = 1810538 | doi = 10.1186/1471-2334-7-8 | doi-access = free }} [97] => [98] => ===Drug formulations=== [99] => {{more citations needed section|reason=no citations in table/chart|date=November 2021}} [100] => {| class = "wikitable" style = "float:right; font-size:90%; margin-left:15px" [101] => |+Pharmaceutical forms of interferons [102] => ! Generic name !! Brand name [103] => |- [104] => | [[Interferon alfa]] || Multiferon [105] => |- [106] => | [[Interferon alpha 2a]] || Roferon A [107] => |- [108] => | [[Interferon alpha 2b]] || Intron A/Reliferon/Uniferon [109] => |- [110] => | Human leukocyte Interferon-alpha (HuIFN-alpha-Le)|| Multiferon [111] => |- [112] => | [[Interferon beta 1a]], liquid form || Rebif [113] => |- [114] => | [[Interferon beta 1a]], lyophilized || Avonex [115] => |- [116] => | [[Interferon beta 1a]], biogeneric (Iran) || Cinnovex [117] => |- [118] => | [[Interferon beta 1b]] || Betaseron / Betaferon [119] => |- [120] => | [[Interferon gamma 1b]] || Actimmune [121] => |- [122] => | [[Peginterferon alfa-2a|PEGylated interferon alpha 2a]] || Pegasys [123] => |- [124] => | [[Peginterferon alfa-2a|PEGylated interferon alpha 2a]] (Egypt) || Reiferon Retard [125] => |- [126] => | [[Peginterferon alfa-2b|PEGylated interferon alpha 2b]] || PegIntron [127] => |- [128] => | [[Ropeginterferon alfa-2b]] || Besremi [129] => |- [130] => | [[Peginterferon alfa-2b|PEGylated interferon alpha 2b]] plus [[ribavirin]] (Canada) || Pegetron [131] => |} [132] => [133] => Several different types of interferons are approved for use in humans. One was first approved for medical use in 1986.{{cite book|last1=Long|first1=Sarah S.|last2=Pickering|first2=Larry K.|last3=Prober|first3=Charles G.|name-list-style=vanc|title=Principles and Practice of Pediatric Infectious Disease|date=2012|publisher=Elsevier Health Sciences|isbn=978-1437727029|page=1502|url=https://books.google.com/books?id=nQ7-o8JAH7kC&pg=PA1502|language=en|access-date=2017-09-01|archive-date=2019-12-29|archive-url=https://web.archive.org/web/20191229144313/https://books.google.com/books?id=nQ7-o8JAH7kC&pg=PA1502|url-status=live}} For example, in January 2001, the [[Food and Drug Administration]] (FDA) approved the use of [[PEGylated]] interferon-alpha in the USA; in this formulation, [[Peginterferon alfa-2b|PEGylated interferon-alpha-2b]] (''Pegintron''), [[polyethylene glycol]] is linked to the interferon molecule to make the interferon last longer in the body. Approval for [[Peginterferon alfa-2a|PEGylated interferon-alpha-2a]] (''Pegasys'') followed in October 2002. These PEGylated drugs are injected once weekly, rather than administering two or three times per week, as is necessary for conventional interferon-alpha. When used with the [[antiviral drug]] [[ribavirin]], PEGylated interferon is effective in treatment of [[hepatitis C]]; at least 75% of people with hepatitis C genotypes 2 or 3 benefit from interferon treatment, although this is effective in less than 50% of people infected with genotype 1 (the more common form of hepatitis C virus in both the U.S. and Western Europe).{{cite journal | vauthors = Jamall IS, Yusuf S, Azhar M, Jamall S | title = Is pegylated interferon superior to interferon, with ribavarin, in chronic hepatitis C genotypes 2/3? | journal = World Journal of Gastroenterology | volume = 14 | issue = 43 | pages = 6627–31 | date = November 2008 | pmid = 19034963 | pmc = 2773302 | doi = 10.3748/wjg.14.6627 | doi-access = free }}{{cite journal | title = NIH Consensus Statement on Management of Hepatitis C: 2002 | journal = NIH Consensus and State-Of-The-Science Statements | volume = 19 | issue = 3 | pages = 1–46 | year = 2002 | pmid = 14768714 }}{{cite journal | vauthors = Sharieff KA, Duncan D, Younossi Z | title = Advances in treatment of chronic hepatitis C: 'pegylated' interferons | journal = Cleveland Clinic Journal of Medicine | volume = 69 | issue = 2 | pages = 155–9 | date = February 2002 | pmid = 11990646 | doi = 10.3949/ccjm.69.2.155 }} Interferon-containing regimens may also include [[Protease inhibitor (pharmacology)|protease inhibitors]] such as [[boceprevir]] and [[telaprevir]]. [134] => [135] => There are also interferon-inducing drugs, notably [[tilorone]]{{cite journal |vauthors=Stringfellow D, Glasgow L |title=Tilorone hydrochloride: an oral interferon-inducing agent |journal=Antimicrob Agents Chemother |volume=2 |issue=2 |pages=73–8 |year=1972 |pmid=4670490 |pmc=444270 |doi=10.1128/aac.2.2.73}} that is shown to be effective against [[Ebola virus]].{{Cite journal|pmid = 29133569|year = 2018|last1 = Ekins|first1 = S.|last2 = Lingerfelt|first2 = M. A.|last3 = Comer|first3 = J. E.|last4 = Freiberg|first4 = A. N.|last5 = Mirsalis|first5 = J. C.|last6 = O'Loughlin|first6 = K.|last7 = Harutyunyan|first7 = A.|last8 = McFarlane|first8 = C.|last9 = Green|first9 = C. E.|last10 = Madrid|first10 = P. B.|title = Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection|journal = Antimicrobial Agents and Chemotherapy|volume = 62|issue = 2|doi = 10.1128/AAC.01711-17|pmc = 5786809}} [136] => [137] => ==History== [138] => {{primary sources section|find=Interferon|find2=history|date=July 2014}} [139] => [[File:SidneyPestka NationalMedalOfTech.jpg|thumbnail|[[Sidney Pestka]] of [[Rutgers University]], seen here receiving the [[National Medal of Technology]].]] [140] => [141] => Interferons were first described in 1957 by [[Alick Isaacs]] and [[Jean Lindenmann]] at the [[National Institute for Medical Research]] in London;{{cite news |first=Gina |last=Kolata |title=Jean Lindenmann, Who Made Interferon His Life's Work, Is Dead at 90 |url=https://www.nytimes.com/2015/01/23/us/jean-lindenmann-made-interferon-his-lifes-work-is-dead-at-90.html?_r=0 |work=[[The New York Times]] |date=2015-01-22 |access-date=2015-02-12 |archive-date=2019-12-27 |archive-url=https://web.archive.org/web/20191227123436/https://www.nytimes.com/2015/01/23/us/jean-lindenmann-made-interferon-his-lifes-work-is-dead-at-90.html?_r=0 |url-status=live }}{{cite journal | vauthors = Isaacs A, Lindenmann J | title = Virus interference. I. The interferon | journal = Proceedings of the Royal Society of London. Series B, Biological Sciences | volume = 147 | issue = 927 | pages = 258–67 | date = September 1957 | pmid = 13465720 | doi = 10.1098/rspb.1957.0048 | bibcode = 1957RSPSB.147..258I | s2cid = 202574492 }}{{cite journal | vauthors = Pestka S | title = The interferons: 50 years after their discovery, there is much more to learn | journal = The Journal of Biological Chemistry | volume = 282 | issue = 28 | pages = 20047–51 | date = July 2007 | pmid = 17502369 | doi = 10.1074/jbc.R700004200 | doi-access = free }} the discovery was a result of their studies of [[viral interference]]. Viral interference refers to the inhibition of virus growth caused by previous exposure of cells to an active or a heat-inactivated virus. Isaacs and Lindenmann were working with a system that involved the inhibition of the growth of live influenza virus in chicken embryo chorioallantoic membranes by heat-inactivated influenza virus. Their experiments revealed that this interference was mediated by a protein released by cells in the heat-inactivated influenza virus-treated membranes. They published their results in 1957 naming the antiviral factor they had discovered ''interferon''. The findings of Isaacs and Lindenmann have been widely confirmed and corroborated in the literature.{{cite book|author=W.E. Stewart II|title=The Interferon System|page=1|date=2013-04-17|publisher=Springer Science & Business Media|isbn=978-3-7091-3432-0}} [142] => [143] => Furthermore, others may have made observations on interferons before the 1957 publication of Isaacs and Lindenmann. For example, during research to produce a more efficient [[vaccine]] for [[smallpox]], Yasu-ichi Nagano and Yasuhiko Kojima—two Japanese [[virology|virologists]] working at the Institute for Infectious Diseases at the [[University of Tokyo]]—noticed inhibition of viral growth in an area of rabbit-skin or testis previously [[inoculate]]d with UV-inactivated virus. They hypothesised that some "viral inhibitory factor" was present in the tissues infected with virus and attempted to isolate and characterize this factor from tissue [[Homogenization (biology)|homogenate]]s.{{cite journal | vauthors = Nagano Y, Kojima Y | title = Pouvoir immunisant du virus vaccinal inactivé par des rayons ultraviolets |trans-title=Immunizing property of vaccinia virus inactivated by ultraviolets rays | language = fr | journal = Comptes Rendus des Séances de la Société de Biologie et de ses Filiales | volume = 148 | issue = 19–20 | pages = 1700–2 | date = October 1954 | pmid = 14364998 |url = https://gallica.bnf.fr/ark:/12148/bpt6k9748814w/f1726.item }} Independently, Monto Ho, in [[John Franklin Enders|John Enders]]'s lab, observed in 1957 that attenuated poliovirus conferred a species specific anti-viral effect in human amniotic cell cultures. They described these observations in a 1959 publication, naming the responsible factor ''viral inhibitory factor'' (VIF).{{cite journal | vauthors = Ho M, Enders JF | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 45 | issue = 3 | pages = 385–9 | date = March 1959 | pmid = 16590396 | pmc = 222571 | doi = 10.1073/pnas.45.3.385| title = An Inhibitor of Viral Activity Appearing in Infected Cell Cultures | bibcode = 1959PNAS...45..385H | doi-access = free }} It took another fifteen to twenty years, using somatic cell genetics, to show that the interferon action gene and interferon gene reside in different human chromosomes.{{cite journal | vauthors = Tan YH, Tischfield J, Ruddle FH | title = The linkage of genes for the human interferon-induced antiviral protein and indophenol oxidase-B traits to chromosome G-21 | journal = The Journal of Experimental Medicine | volume = 137 | issue = 2 | pages = 317–30 | date = February 1973 | pmid = 4346649 | pmc = 2139494 | doi = 10.1084/jem.137.2.317 }}{{cite journal | vauthors = Tan YH | title = Chromosome 21 and the cell growth inhibitory effect of human interferon preparations | journal = Nature | volume = 260 | issue = 5547 | pages = 141–3 | date = March 1976 | pmid = 176593 | doi = 10.1038/260141a0 | bibcode = 1976Natur.260..141T | s2cid = 4287343 }}{{cite journal | vauthors = Meager A, Graves H, Burke DC, Swallow DM | title = Involvement of a gene on chromosome 9 in human fibroblast interferon production | journal = Nature | volume = 280 | issue = 5722 | pages = 493–5 | date = August 1979 | pmid = 460428 | doi = 10.1038/280493a0 | bibcode = 1979Natur.280..493M | s2cid = 4315307 }} The purification of human beta interferon did not occur until 1977. Y.H. Tan and his co-workers purified and produced biologically active, radio-labeled human beta interferon by superinducing the interferon gene in fibroblast cells, and they showed its active site contains tyrosine residues.{{cite journal | vauthors = Berthold W, Tan C, Tan YH | title = Chemical modifications of tyrosyl residue(s) and action of human-fibroblast interferon | journal = European Journal of Biochemistry | volume = 87 | issue = 2 | pages = 367–70 | date = June 1978 | pmid = 678325 | doi = 10.1111/j.1432-1033.1978.tb12385.x | doi-access = free }}{{cite journal | vauthors = Berthold W, Tan C, Tan YH | title = Purification and in vitro labeling of interferon from a human fibroblastoid cell line | journal = The Journal of Biological Chemistry | volume = 253 | issue = 14 | pages = 5206–12 | date = July 1978 | doi = 10.1016/S0021-9258(17)34678-1 | pmid = 670186 | doi-access = free }} Tan's laboratory isolated sufficient amounts of human beta interferon to perform the first amino acid, sugar composition and N-terminal analyses.{{cite journal | vauthors = Tan YH, Barakat F, Berthold W, Smith-Johannsen H, Tan C | title = The isolation and amino acid/sugar composition of human fibroblastoid interferon | journal = The Journal of Biological Chemistry | volume = 254 | issue = 16 | pages = 8067–73 | date = August 1979 | doi = 10.1016/S0021-9258(18)36051-4 | pmid = 468807 | doi-access = free }} They showed that human beta interferon was an unusually hydrophobic glycoprotein. This explained the large loss of interferon activity when preparations were transferred from test tube to test tube or from vessel to vessel during purification. The analyses showed the reality of interferon activity by chemical verification.{{cite journal | vauthors = Zoon KC, Smith ME, Bridgen PJ, Anfinsen CB, Hunkapiller MW, Hood LE | title = Amino terminal sequence of the major component of human lymphoblastoid interferon | journal = Science | volume = 207 | issue = 4430 | pages = 527–8 | date = February 1980 | pmid = 7352260 | doi = 10.1126/science.7352260 | bibcode = 1980Sci...207..527Z }}{{cite journal | vauthors = Okamura H, Berthold W, Hood L, Hunkapiller M, Inoue M, Smith-Johannsen H, Tan YH | title = Human fibroblastoid interferon: immunosorbent column chromatography and N-terminal amino acid sequence | journal = Biochemistry | volume = 19 | issue = 16 | pages = 3831–5 | date = August 1980 | pmid = 6157401 | doi = 10.1021/bi00557a028 }}{{cite journal | vauthors = Knight E, Hunkapiller MW, Korant BD, Hardy RW, Hood LE | title = Human fibroblast interferon: amino acid analysis and amino terminal amino acid sequence | journal = Science | volume = 207 | issue = 4430 | pages = 525–6 | date = February 1980 | pmid = 7352259 | doi = 10.1126/science.7352259 | bibcode = 1980Sci...207..525K }} The purification of human alpha interferon was not reported until 1978. A series of publications from the laboratories of [[Sidney Pestka]] and Alan Waldman between 1978 and 1981, describe the purification of the type I interferons IFN-α and IFN-β. By the early 1980s, genes for these interferons had been cloned, adding further definitive proof that interferons were responsible for interfering with viral replication.{{cite journal | vauthors = Weissenbach J, Chernajovsky Y, Zeevi M, Shulman L, Soreq H, Nir U, Wallach D, Perricaudet M, Tiollais P, Revel M | title = Two interferon mRNAs in human fibroblasts: in vitro translation and Escherichia coli cloning studies | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 12 | pages = 7152–6 | date = December 1980 | pmid = 6164058 | pmc = 350459 | doi = 10.1073/pnas.77.12.7152 | bibcode = 1980PNAS...77.7152W | doi-access = free }}{{cite journal | vauthors = Taniguchi T, Fujii-Kuriyama Y, Muramatsu M | title = Molecular cloning of human interferon cDNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 7 | pages = 4003–6 | date = July 1980 | pmid = 6159625 | pmc = 349756 | doi = 10.1073/pnas.77.7.4003 | bibcode = 1980PNAS...77.4003T | doi-access = free }} Gene cloning also confirmed that IFN-α was encoded by a family of many related genes.{{cite journal | vauthors = Nagata S, Mantei N, Weissmann C | title = The structure of one of the eight or more distinct chromosomal genes for human interferon-alpha | journal = Nature | volume = 287 | issue = 5781 | pages = 401–8 | date = October 1980 | pmid = 6159536 | doi = 10.1038/287401a0 | bibcode = 1980Natur.287..401N | s2cid = 29500779 }} The type II IFN (IFN-γ) gene was also isolated around this time.{{cite journal | vauthors = Gray PW, Goeddel DV | title = Structure of the human immune interferon gene | journal = Nature | volume = 298 | issue = 5877 | pages = 859–63 | date = August 1982 | pmid = 6180322 | doi = 10.1038/298859a0 | bibcode = 1982Natur.298..859G | s2cid = 4275528 }} [144] => [145] => Interferon was first synthesized manually at [[Rockefeller University]] in the lab of Dr. [[Bruce Merrifield]], using [[solid phase peptide synthesis]], one amino acid at a time. He later won the Nobel Prize in chemistry. Interferon was scarce and expensive until 1980, when the interferon [[gene]] was inserted into [[bacterium|bacteria]] using [[recombinant DNA technology]], allowing mass cultivation and purification from [[Microbiological culture#Bacterial culture|bacterial cultures]]{{cite journal | vauthors = Nagata S, Taira H, Hall A, Johnsrud L, Streuli M, Ecsödi J, Boll W, Cantell K, Weissmann C | title = Synthesis in E. coli of a polypeptide with human leukocyte interferon activity | journal = Nature | volume = 284 | issue = 5754 | pages = 316–20 | date = March 1980 | pmid = 6987533 | doi = 10.1038/284316a0 | bibcode = 1980Natur.284..316N | s2cid = 4310807 }} or derived from [[yeast]]s. Interferon can also be produced by recombinant mammalian cells.{{cite patent | inventor = Tan YH, Hong WJ | title = Gene expression in mammalian cells. | country = US | number = 6207146 | gdate = 2001 | status = patent }} [146] => Before the early 1970s, large scale production of human interferon had been pioneered by Kari Cantell. He produced large amounts of human alpha interferon from large quantities of human white blood cells collected by the Finnish Blood Bank.{{Cite book | author = Cantell K | title = The story of interferon: the ups and downs in the life of a scientis | date = 1998 | publisher = World Scientific | location = Singapore; New York | isbn = 978-981-02-3148-4 }} Large amounts of human beta interferon were made by superinducing the beta interferon gene in human fibroblast cells.{{cite journal | vauthors = Tan YH, Armstrong JA, Ke YH, Ho M | title = Regulation of cellular interferon production: enhancement by antimetabolites | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 67 | issue = 1 | pages = 464–71 | date = September 1970 | pmid = 5272327 | pmc = 283227 | doi = 10.1073/pnas.67.1.464 | bibcode = 1970PNAS...67..464T | doi-access = free }}{{cite patent | inventor = Ho M, Armstrong JA, Ke YH, Tan YH | title = Interferon Production | country = US | status = patent | number = 3773924 | gdate = 1973}} [147] => [148] => Cantell's and Tan's methods of making large amounts of natural interferon were critical for chemical characterisation, clinical trials and the preparation of small amounts of interferon messenger RNA to clone the human alpha and beta interferon genes. The superinduced human beta interferon messenger RNA was prepared by Tan's lab for [[Cetus Corporation|Cetus]]. to clone the human beta interferon gene in bacteria and the recombinant interferon was developed as 'betaseron' and approved for the treatment of MS. Superinduction of the human beta interferon gene was also used by Israeli scientists to manufacture human beta interferon. [149] => [150] => == Human interferons == [151] => {{columns-list|colwidth=22em| [152] => * [[IFNA1]] [153] => * [[IFNA2]] [154] => * [[IFNA4]] [155] => * [[IFNA5]] [156] => * [[IFNA6]] [157] => * [[IFNA7]] [158] => * [[IFNA8]] [159] => * [[IFNA10]] [160] => * [[IFNA13]] [161] => * [[IFNA14]] [162] => * [[IFNA16]] [163] => * [[IFNA17]] [164] => * [[IFNA21]] [165] => * [[IFNB1]] [166] => * IFNW [167] => * IFNE1 [168] => * [[IFNK]] [169] => }} {{cite journal | vauthors = Bekisz J, Schmeisser H, Hernandez J, Goldman ND, Zoon KC | title = Human interferons alpha, beta and omega | journal = Growth Factors | volume = 22 | issue = 4 | pages = 243–51 | date = December 2004 | pmid = 15621727 | doi = 10.1080/08977190400000833 | s2cid = 84918367 | url = https://zenodo.org/record/1234455 }} [170] => [171] => == Teleost fish interferons == [172] => {{columns-list|colwidth=22em| [173] => * [[IFNa]] [174] => * [[IFNb]] [175] => * [[IFNc]] [176] => * [[IFNd]] [177] => * [[IFNe]] [178] => * [[IFNf]] [179] => * [[IFNg (gamma)]] [180] => * [[IFNh]] [181] => }}{{cite journal | vauthors = Laghari ZA, Chen SN, Li L, Huang B, Gan Z, Zhou Y, Huo HJ, Hou J, Nie P | 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 | year = 2018 | pmid = 29432791 | doi = 10.1016/j.dci.2018.02.008 | s2cid = 3455413 }}{{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| year = 2016 | pmid = 27827855 | pmc = 5127012 | doi = 10.3390/v8110298 | doi-access = free }} [182] => [183] => ==References== [184] => {{reflist}} [185] => [186] => ==Further reading== [187] => * {{cite book |doi=10.1007/978-3-319-07758-1_7 |pmc=7123835 |chapter=Interferons |title=Viruses and Man: A History of Interactions |year=2014 |last1=Taylor |first1=Milton W. |pages=101–119 |isbn=978-3-319-07757-4 }} [188] => [189] => ==External links== [190] => * {{Commons category-inline|Interferons}} [191] => [192] => {{Antivirals}} [193] => {{Ophthalmological anti-infectives}} [194] => {{Cytokines}} [195] => {{Cytokine receptor modulators}} [196] => {{Portal bar | Medicine | Viruses}} [197] => {{Authority control}} [198] => [199] => [[Category:Cytokines]] [200] => [[Category:Antiviral drugs]] [] => )
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Interferon

Interferons are a group of proteins produced by cells in response to a viral infection. They play a vital role in the immune response by inhibiting the replication of viruses, suppressing tumor growth, and regulating various immune functions.

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They play a vital role in the immune response by inhibiting the replication of viruses, suppressing tumor growth, and regulating various immune functions. This Wikipedia page provides an overview of interferons, detailing their discovery, structure, types, and mechanisms of action. The page begins with a historical account of interferon research, highlighting the early observations that led to their identification. It then delves into the various types of interferons, including alpha, beta, gamma, lambda, and sigma, and provides insight into their specific functions and distribution within the body. The structure and signaling pathways of interferons are explored in detail. The page elucidates the structural features that distinguish different types of interferons and explains how they interact with specific receptors on cell surfaces to trigger a cascade of intracellular signaling events. Additionally, the molecular mechanisms responsible for interferon-induced antiviral and immune responses are explained, shedding light on the complex interplay between interferons and host cells. The medical applications of interferons are also discussed, ranging from their use in treating viral infections like hepatitis B and C to their role as therapeutic agents against certain types of cancers. Furthermore, the limitations and side effects associated with interferon therapy are addressed, along with ongoing research and potential avenues for improvement. Overall, this Wikipedia page offers a comprehensive overview of interferons, serving as a valuable resource for those seeking a better understanding of these essential components of the immune system.

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