Interferon

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"IFN" redirects here. For other uses, see IFN (disambiguation).
Interferon type I (α/β/δ...)
SCOP2
1au1 / SCOPe / SUPFAM
CDDcd00095
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Interferon type II (γ)
SCOP2
d1d9ca_ / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Interferon type III (λ)
Identifiers
SymbolIL28A
PfamPF15177
InterProIPR029177
CATH3og6A00
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Interferons (IFNs,

host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells
to heighten their anti-viral defenses.

IFNs belong to the large class of

cytokines
.

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.

Types of interferon

Based on the type of receptor through which they signal, human interferons have been classified into three major types.

  • 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 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.[7] Overall, IFN-α can be used to treat hepatitis B and C infections, while IFN-β can be used to treat multiple sclerosis.[3]
  • IFNGR2 chains.[3]
  • IFNLR1 (also called CRF2-12). Although discovered more recently than type I and type II IFNs,[9] recent information demonstrates the importance of Type III IFNs in some types of virus or fungal infections.[10][11][12]

In general, type I and II interferons are responsible for regulating and activating the immune response.

NK cells.[citation needed
]

Function

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. 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

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.[13][14]
They also limit viral spread by increasing p53 activity, which kills virus-infected cells by promoting apoptosis.[15][16] The effect of IFN on p53 is also linked to its protective role against certain cancers.[15]

Another function of interferons is to up-regulate

interleukins, among others) that signal to and co-ordinate the activity of other immune cells.[17][18][19]

Interferons can also suppress angiogenesis by down regulation of angiogenic stimuli deriving from tumor cells. They also suppress the proliferation of endothelial cells. Such suppression causes a decrease in tumor angiogenesis, a decrease in its vascularization and subsequent growth inhibition. Interferons, such as interferon gamma, directly activate other immune cells, such as macrophages and natural killer cells.[17][18][19]

Induction of interferons

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

MDA5
, can trigger release of IFNs. Toll Like Receptor 3 (
tumor necrosis factor and colony-stimulating factor, can also enhance interferon production.[21]

Downstream signaling

By interacting with their specific receptors, IFNs activate signal transducer and activator of transcription (STAT) complexes; STATs are a family of transcription factors 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.[22]

STAT activation initiates the most well-defined cell signaling pathway for all IFNs, the classical

promoters of certain genes, 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.[22] A collection of known ISGs is available on Interferome, a curated online database of ISGs (www.interferome.org);[23] Additionally, STAT homodimers or heterodimers form from different combinations of STAT-1, -3, -4, -5, or -6 during IFN signaling; these dimers initiate gene transcription by binding to IFN-activated site (GAS) elements in gene promoters.[22] 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.[22]

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

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.[22]

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.[24] 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]

Viral resistance to interferons

Many viruses have evolved mechanisms to resist interferon activity.

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.[32] 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,[33][34] although mechanisms of acquired and intrinsic resistance to interferon therapy in HCV are polyfactorial.[35][36]

Coronavirus response

SARS-CoV, which itself is a weak IFN-I inducer in human cells.[37][38] SARS-CoV-2 limits the IFN-III response as well.[39] Reduced numbers of plasmacytoid dendritic cells with age is associated with increased COVID-19 severity, possibly because these cells are substantial interferon producers.[40]

Ten percent of patients with life-threatening COVID-19 have autoantibodies against type I interferon.[40]

Delayed IFN-I response contributes to the pathogenic inflammation (cytokine storm) seen in later stages of COVID-19 disease.[41] Application of IFN-I prior to (or in the very early stages of) viral infection can be protective,[37] as can treatment with pegylated IFN-λIII,[42] which should be validated in randomized clinical trials.[41]

Interferon therapy

Three vials filled with human leukocyte interferon

Diseases

autoimmune disorder. This treatment may help in reducing attacks in relapsing-remitting multiple sclerosis[43] and slowing disease progression and activity in secondary progressive multiple sclerosis.[44]

Interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for some cancers.

chronic myeloid leukemia, nodular lymphoma, and cutaneous T-cell lymphoma.[45] Patients with recurrent melanomas receive recombinant IFN-α2b.[46]

Both

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[55] 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.[56]

Unconfirmed results suggested that interferon eye drops may be an effective treatment for people who have

herpes simplex virus epithelial keratitis, a type of eye infection.[57] 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.[57] Unconfirmed results suggested that the combination of interferon and an antiviral agent may speed the healing process compared to antiviral therapy alone.[57]

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.[58]

Drug formulations

Pharmaceutical forms of interferons
Generic name Brand name
Interferon alfa Multiferon
Interferon alpha 2a
 Roferon A
Interferon alpha 2b
 Intron A/Reliferon/Uniferon
Human leukocyte Interferon-alpha (HuIFN-alpha-Le) Multiferon
Interferon beta 1a
, liquid form		 Rebif
Interferon beta 1a
, lyophilized		 Avonex
Interferon beta 1a
, biogeneric (Iran)		 Cinnovex
Interferon beta 1b
 Betaseron / Betaferon
Interferon gamma 1b
 Actimmune
PEGylated interferon alpha 2a Pegasys
PEGylated interferon alpha 2a (Egypt) Reiferon Retard
PEGylated interferon alpha 2b PegIntron
Ropeginterferon alfa-2b Besremi
PEGylated interferon alpha 2b plus ribavirin (Canada) Pegetron

Several different types of interferons are approved for use in humans. One was first approved for medical use in 1986.

PEGylated interferon-alpha in the USA; in this formulation, PEGylated interferon-alpha-2b (Pegintron), polyethylene glycol is linked to the interferon molecule to make the interferon last longer in the body. Approval for 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).[60][61][62] Interferon-containing regimens may also include protease inhibitors such as boceprevir and telaprevir
.

There are also interferon-inducing drugs, notably

Ebola virus.[64]

History

National Medal of Technology
.

Interferons were first described in 1957 by Alick Isaacs and Jean Lindenmann at the National Institute for Medical Research in London;[65][66][67] 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.[66] The findings of Isaacs and Lindenmann have been widely confirmed and corroborated in the literature.[68]

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

inoculated 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 homogenates.[69] Independently, Monto Ho, in 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).[70] 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.[71][72][73] 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.[74][75] Tan's laboratory isolated sufficient amounts of human beta interferon to perform the first amino acid, sugar composition and N-terminal analyses.[76] 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.[76][77][78][79] 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.[67] By the early 1980s, genes for these interferons had been cloned, adding further definitive proof that interferons were responsible for interfering with viral replication.[80][81] Gene cloning also confirmed that IFN-α was encoded by a family of many related genes.[82] The type II IFN (IFN-γ) gene was also isolated around this time.[83]

Interferon was first synthesized manually at

recombinant DNA technology, allowing mass cultivation and purification from bacterial cultures[84] or derived from yeasts. Interferon can also be produced by recombinant mammalian cells.[85]
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.[86] Large amounts of human beta interferon were made by superinducing the beta interferon gene in human fibroblast cells.[87][88]

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. 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.

Human interferons

[6][89]

Teleost fish interferons

[90][91]

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Further reading

External links
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