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Interferons (IFNs) Family


Overview

Interferons (IFNs) are a group of signaling proteins made and released by host cells in response to the presence of several pathogens, such as viruses, bacteria, parasites, and tumor cells. 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 proteins known as cytokines/molecules used for communication between cells to trigger the protective defenses of the immune system that help eradicate pathogens. Interferons are named for their ability to "interfere" with viral replication by protecting cells from virus infections. IFNs also have various other functions: they activate immune cells, such as natural killer cells and macrophages; 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.

Members of IFNs

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.

Table 1. IFNs family related products

IFNs Type I IFN-α IFNA1 IFNA2
IFNA3 IFNA4 IFNA5
IFNA6 IFNA7 IFNA8
IFNA10 IFNA13 IFNA14
IFNA16 IFNA17 IFNA21
IFNB1 IFNE IFNK
IFNW1 IFNZ  
IFNs Type II IFN-γ IFNG  
IFNs Type III IFNL1 / IL29 IFNL2 / IL28A IFNL3 / IL28B
IFNs Receptors IFNAR1 IFNAR2 IFNGR1
IFNGR2 IFNLR1 IL10RB

  • Interferon type I

All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α/β receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. The type I interferons present in humans are IFN-α, IFN-β, IFN-ε, IFN-κ and IFN-ω.

Interferons (IFNs) Family

Figure 1. The three-dimensional structure of human interferon beta.

IFN-α The IFN-α proteins are produced by leukocytes. They are mainly involved in innate immune response 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.
IFN-β 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) (a gene designated IFN-β2 is actually IL-6). IFN-β1 is used as a treatment for multiple sclerosis as it reduces the relapse rate. IFN-β1 is not an appropriate treatment for patients with progressive, non-relapsing forms of multiple sclerosis.
IFN-κ Interferon kappa, also known as IFN-kappa, is a protein that in humans is encoded by the IFNK gene. IFN-kappa is a member of the type I interferon family. Type I interferons are a group of related glycoproteins that play an important role in host defenses against viral infections. This protein is expressed in keratinocytes and the gene is found on chromosome 9, adjacent to the type I interferon cluster.
IFN-ω IFN-ω, although having only one functional form described to date (IFNW1), has several pseudogenes: IFNWP2, IFNWP4, IFNWP5, IFNWP9, IFNWP15, IFNWP18, and IFNWP19 in humans. Many non-primate placental mammals express multiple IFN-ω subtypes.

  • Interferon type II

A sole member makes up the type II interferons (IFNs) that is called IFN-γ (gamma). Mature IFN-γ is an anti-parallel homodimer, which binds to the IFN-γ receptor (IFNGR) complex to elicit a signal within its target cell. IFNGR is made up of two subunits and each of molecules designates IFNGR1 and IFNGR2.

IFN-γ is involved in the regulation of the immune and inflammatory responses; in humans, there is only one type of interferon-gamma. It is produced in activated T-cells and natural killer cells. IFN-γ has some anti-viral and anti-tumor effects, but these are generally weak. However, this cytokine potentiates the effects of the type I IFNs. IFN-γ released by Th1 cells recruits leukocytes to a site of infection, resulting in increased inflammation. It also stimulates macrophages to kill bacteria that have been engulfed. IFN-γ released by Th1 cells is also important in regulating the Th2 response. As IFN-γ is vitally implicated in the regulation of immune response, its production can lead to autoimmune disorders.

Interferons (IFNs) Family

Figure 2. The tridimensional structure of human interferon gamma.

  • Interferon type III

The recently classified type III interferon group consists of three IFN-λ (lambda) molecules called IFN-λ1, IFN-λ2 and IFN-λ3 (also called IL29, IL28A and IL28B respectively). These IFNs signals through a receptor complex consist of IL10R2 (also called CRF2-4) and IL28RA (also called IFNLR1, CRF2-12). Recently, a new protein with a similar function related to IFN-λ3 was found around the same genomic locus and was designated IFN-λ4. Its intracellular signaling was through IFNLR1 and therefore thought to be a type III interferon. However, the evidence of its in vivo bioactivity is still debatable.


IL29

Interleukin-29 (IL-29) is a protein that in humans is encoded by the IL29 gene that resides on chromosome 19. It is a member of the helical cytokine family and is a type III interferon. It is also known as IFNλ1 and is highly similar in amino acid sequence to the IL-28, the other type III interferon. IL-29 plays an important role in host defenses against microbes and its gene is highly upregulated in cells infected with viruses. IL29 is not present in the mouse genome.
IL28 Interleukin-28 (IL-28) is a cytokine that comes in two isoforms, IL-28A and IL-28B, and plays a role in immune defense against viruses, including the induction of an "antiviral state" by turning on Mx proteins, 2',5'-oligoadenylate synthetase as well as ISGF3G (Interferon Stimulated Gene Factor 3). IL-28A and IL-28B belong to the type III interferon family of cytokines and are highly similar (in amino acid sequence) to IL-29. Their classification as Interferons is due to their ability to induce an antiviral state, while their additional classification as cytokines is due to their chromosomal location as well as the fact that they are encoded by multiple exons, as opposed to a single exon, as most type-I IFNs are.

Cellular functions

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 prepare neighboring cells against a potential infection by the virus by releasing interferons. In response to interferon, cells produce large amounts of an enzyme known as protein kinase R (PKR). This enzyme 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 destroys both the virus 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. They also limit viral spread by increasing p53 activity, which kills virus-infected cells by promoting apoptosis. The effect of IFN on p53 is also linked to its protective role against certain cancers.

Another function of interferons is to upregulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. Higher MHC I expression increases presentation of viral peptides to cytotoxic T cells, while the immunoproteasome processes viral peptides for loading onto the MHC I molecule, thereby increasing the recognition and killing of infected cells. Higher MHC II expression increases presentation of viral peptides to helper T cells; these cells release cytokines (such as more interferons and interleukins, among others) that signal to and co-ordinate the activity of other immune cells. Interferons, such as interferon gamma, directly activate other immune cells, macrophages and natural killer cells.

Interferons (IFNs) Family

Figure 3. Line and cartoon representation of an IFNγ dimer.

Role in disease

Interferon beta-1a and interferon beta-1b are used to treat and control multiple sclerosis, an autoimmune disorder. This treatment is effective for reducing attacks in relapsing-remitting multiple sclerosis and slowing disease progression and activity in secondary progressive multiple sclerosis.

Interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for some cancers. This treatment can be used in hematological malignancy; leukemia and lymphomas including hairy cell leukemia, chronic myeloid leukemia, nodular lymphoma, and cutaneous T-cell lymphoma. Patients with recurrent melanomas receive recombinant IFN-α2b. Both hepatitis B and hepatitis C are treated with IFN-α, often in combination with other antiviral drugs. Some of those treated with interferon have a sustained virological response and can eliminate hepatitis virus. The most harmful strain—hepatitis C genotype I virus—can be treated with a 60-80% success rate with the current standard-of-care treatment of interferon-α, ribavirin and recently approved protease inhibitors such as Telaprevir (Incivek) May 2011, Boceprevir (Victrelis) May 2011 or the nucleotide analog polymerase inhibitor Sofosbuvir (Sovaldi) December 2013. Biopsies of patients given the treatment show reductions in liver damage and cirrhosis. Some evidence shows giving interferon immediately following infection can prevent chronic hepatitis C, although diagnosis early in infection is difficult since physical symptoms are sparse in early hepatitis C infection. Control of chronic hepatitis C by IFN is associated with reduced hepatocellular carcinoma.

There is low-quality evidence suggesting that interferon eye drops may be an effective treatment for people who have herpes simplex virus epithelial keratitis, a type of eye infection. 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. Low-quality evidence suggests that the combination of interferon and an antiviral agent may speed the healing process compared to antiviral therapy alone.

References:

1. De Andrea M, Ravera R, Gioia D, Gariglio M, Landolfo S (2002). "The interferon system: an overview". European Journal of Paediatric Neurology. 6 Suppl A (6): A41–6; discussion A55–8.
2. Levy DE, Marié IJ, Durbin JE (December 2011). "Induction and function of type I and III interferon in response to viral infection". Current Opinion in Virology. 1 (6): 476–86.
3. Hermant P, Michiels T (2014). "Interferon-λ in the context of viral infections: production, response and therapeutic implications". Journal of Innate Immunity. 6 (5): 563–74.
4. Navratil V, de Chassey B, Meyniel L, Pradezynski F, André P, Rabourdin-Combe C, Lotteau V (July 2010). "System-level comparison of protein-protein interactions between viruses and the human type I interferon system network". Journal of Proteome Research. 9 (7): 3527–36.
5. Sharieff KA, Duncan D, Younossi Z (February 2002). "Advances in treatment of chronic hepatitis C: 'pegylated' interferons". Cleveland Clinic Journal of Medicine. 69 (2): 155–9.
6. Tan YH, Tischfield J, Ruddle FH (February 1973). "The linkage of genes for the human interferon-induced antiviral protein and indophenol oxidase-B traits to chromosome G-21". The Journal of Experimental Medicine. 137 (2): 317–30.

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