Interferon

Interferon

Discussion
Ask a question about 'Interferon'
Start a new discussion about 'Interferon'
Answer questions from other users
Full Discussion Forum
 
Encyclopedia
Interferons are protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s made and released by host cells in response to the presence of pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

s—such as virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

es, bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

, or parasites—or tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

 cells. They allow communication between cells to trigger the protective defenses of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 that eradicate pathogens or tumors.

IFNs belong to the large class of glycoproteins known as cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s. Interferons are named after their ability to "interfere" with viral replication
Viral replication
Viral replication is the term used by virologists to describe the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. From the perspective of the virus, the purpose of viral replication is...

 within host cells. IFNs have other functions: they activate immune cells, such as natural killer cell
Natural killer cell
Natural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...

s and macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s; they increase recognition of infection or tumor cells by up-regulating antigen presentation
Antigen presentation
Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells....

 to T lymphocytes; and they increase the ability of uninfected host cells to resist new infection by virus. Certain host symptoms, such as aching muscles and fever, are related to the production of IFNs during infection.

About ten distinct IFNs have been identified in mammals; seven of these have been described for humans. They are typically divided among three IFN classes: Type I IFN, Type II IFN, and Type III IFN. IFNs belonging to all IFN classes are very important for fighting viral infections.

Types of interferon


Based on the type of receptor through which they signal, human interferons have been classified into three major types.
  • Interferon type I
    Interferon type I
    Human type I interferons comprise a vast and growing group of IFN proteins.All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor that consists of IFNAR1 and IFNAR2 chains....

    : All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor (IFNAR
    Interferon-alpha/beta receptor
    The interferon-α/β receptor is a receptor which binds type I interferons including interferon-α and -β. It is a heteromeric receptor composed of one chain with two subunits referred to as IFNAR1 and IFNAR2. It is a cell surface receptor. Binding of cytokine follows a JAK-STAT signaling pathway...

    ) that consists of IFNAR1
    IFNAR1
    Interferon-alpha/beta receptor alpha chain is a protein that in humans is encoded by the IFNAR1 gene.-Interactions:IFNAR1 has been shown to interact with STAT2, Tyrosine kinase 2 and PRMT1.-Further reading:...

     and IFNAR2
    IFNAR2
    Interferon-alpha/beta receptor beta chain is a protein that in humans is encoded by the IFNAR2 gene.-Interactions:IFNAR2 has been shown to interact with STAT2, STAT1, GNB2L1 and IFNA2.-Further reading:...

     chains. The type I interferons present in humans are IFN-α, IFN-β and IFN-ω.

  • Interferon type II
    Interferon type II
    A sole member makes up the type II IFNs that is called IFN-γ . Mature IFN-γ is an anti-parallel homodimer, which binds to the IFN-γ receptor complex to elicit a signal within its target cell...

    : Binds to IFNGR that consists of IFNGR1 and IFNGR2 chains. In humans this is IFN-γ.

  • Interferon type III
    Interferon type III
    The recently classified type III interferon group consists of three IFN-λ molecules called IFN-λ1, IFN-λ2 and IFN-λ3 . These IFNs signal through a receptor complex consisting of IL10R2 and IFNLR1...

    : Signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12). Acceptance of this classification is less universal than that of type I and type II, and unlike the other two, it is not currently included in Medical Subject Headings
    Medical Subject Headings
    Medical Subject Headings is a comprehensive controlled vocabulary for the purpose of indexing journal articles and books in the life sciences; it can also serve as a thesaurus that facilitates searching...

    .

Function


All interferons share several common effects; they are antiviral
Antiviral
Antiviral may refer to:*Antiviral drug*Antiviral protein*Antivirus software*Antiviral Therapy, an academic journal...

 agents and can fight tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

s.

As an infected cell dies from a cytolytic
Cytolysis
Cytolysis, or osmotic lysis, occurs when a cell bursts due to an osmotic imbalance that has caused excess water to move into the cell. It occurs in a hypotonic environment, where water diffuses into the cell and causes its volume to increase. If the volume of water exceeds the cell membrane's...

 virus, viral particles are released that can infect nearby cells. However, the infected cell can warn neighboring cells of a viral presence by releasing interferon. The neighboring cells, in response to interferon, produce large amounts of an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 known as protein kinase R
Protein kinase R
Protein kinase RNA-activated also known as protein kinase R , interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 is an enzyme that in humans is encoded by the EIF2AK2 gene.PKR protects against viral...

 (PKR). This enzyme phosphorylates
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

 a protein known as eIF-2 in response to new viral infections; eIF-2 is a eukaryotic translation initiation factor that forms an inactive complex with another protein, called eIF2B
EIF2B
eIF2B is a protein found in eukaryotes. It is the guanine nucleotide exchange factor for the eukaryotic initiation factor 2 and therefore converts the inactive eIF2-GDP to the active eIF2-GTP...

, to reduce protein synthesis within the cell. Another cellular enzyme, RNAse L
RNAse L
RNase L is an interferon-induced ribonuclease which, upon activation, destroys all RNA within the cell .- Production and Activation :...

—also induced following PKR activation—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.
They also limit viral spread by increasing p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...

 activity, which kills virus-infected cells by promoting apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

. 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 cell
Cytotoxic T cell
A cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...

s and natural killer 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, such as macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s and natural killer cell
Natural killer cell
Natural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...

s.

Induction of interferons


Production of interferons predominantly occurs in response to microbes, such as viruses and bacteria, and their products. Binding of molecules uniquely found in microbes—viral glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

s, viral RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

, bacterial endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...

 (lipopolysaccharide), bacterial flagella, CpG motifs--by pattern recognition receptor
Pattern recognition receptor
Pattern recognition receptors are a primitive part of the immune system. They are proteins expressed by cells of the innate immune system to identify pathogen-associated molecular patterns , which are associated with microbial pathogens or cellular stress, as well as damage-associated molecular...

s, such as membrane bound Toll like receptors or the cytoplasmic receptors RIG-I
DDX58
Probable ATP-dependent RNA helicase DDX58 is an enzyme that in humans is encoded by the DDX58 gene. It codes for a protein called retinoic acid-inducible gene 1 protein , also known as DEAD-box protein 58 , which is a cell receptor found in the cytoplasm of cells...

 or MDA5
IFIH1
Interferon-induced helicase C domain-containing protein 1, also known as MDA5 , is an enzyme that in humans is encoded by the IFIH1 gene...

, can trigger release of IFNs.
Toll Like Receptor 3 (TLR3
TLR 3
Toll-like receptor 3 also known as CD283 is a protein that in humans is encoded by the TLR3 gene...

) is important for inducing interferon in response to the presence of double-stranded RNA viruses
Double-stranded RNA viruses
Double-stranded RNA viruses are a diverse group of viruses that vary widely in host range , genome segment number , and virion organization...

; the ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

 for this receptor is double-stranded RNA (dsRNA). After binding dsRNA, this receptor activates the transcription factors IRF3
IRF3
Interferon regulatory factor 3, also known as IRF3, is an interferon regulatory factor.- Function :IRF3 is a member of the interferon regulatory transcription factor family. IRF3 was originally discovered as a homolog of IRF1 and IRF2...

 and NF-κB, which are important for initiating synthesis of many inflammatory proteins. Release of IFN from cells is also induced by mitogen
Mitogen
A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis. A mitogen is usually some form of a protein.Mitogenesis is the induction of mitosis, typically via a mitogen....

s. Other cytokines, such as interleukin 1, interleukin 2
Interleukin 2
Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...

, interleukin-12, tumor necrosis factor and colony-stimulating factor
Colony-stimulating factor
Colony-stimulating factors are secreted glycoproteins that bind to receptor proteins on the surfaces of hemopoietic stem cells, thereby activating intracellular signaling pathways that can cause the cells to proliferate and differentiate into a specific kind of blood cell Colony-stimulating...

, can also enhance interferon production.

Downstream signaling


By interacting with their specific receptors, IFNs activate signal transducer and activator of transcription (STAT
STAT protein
The STAT protein regulates many aspects of growth, survival and differentiation in cells...

) complexes; STATs are a family of transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

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.

STAT activation initiates the most well-defined cell signaling pathway for all IFNs, the classical Janus kinase
Janus kinase
Janus kinase is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 & 2 , but were ultimately published as "Janus kinase"...

-STAT (JAK-STAT) signaling pathway. In this pathway, JAKs associate with IFN receptors and, following receptor engagement with IFN, phosphorylate
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

 both STAT1
STAT1
STAT1 is a member of the Signal Transducers and Activators of Transcription family of transcription factors. STAT1 is involved in upregulating genes due to a signal by either type I, type II or type III interferons...

 and STAT2
STAT2
Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene.-Interactions:STAT2 has been shown to interact with MED14, CREB-binding protein, SMARCA4, STAT1, IFNAR2, IFNAR1 and ISGF3G.-Further reading:...

. As a result, an IFN-stimulated gene factor 3 (ISGF3) complex forms — this contains STAT1, STAT2 and a third transcription factor called IRF9
ISGF3G
Interferon regulatory factor 9 is a protein that in humans is encoded by the IRF9 gene.-Interactions:ISGF3G has been shown to interact with STAT2 and STAT1....

 — and moves into the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

. Inside the nucleus, the ISGF3 complex binds to specific nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...

 sequences called IFN-stimulated response elements (ISREs) in the promoters of certain gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

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. Interferome
Interferome
Interferome is an online bioinformatics database of interferon regulated genes . These Interferon Regulated Genes are also known as Interferon Stimulated Genes . The database contains information on type I , type II and type III regulated genes and is regularly updated...

 is a curated online database of ISGs (www.interferome.org); Additionally, STAT homodimers or heterodimers form from different combinations of STAT-1, -3, -4, -5, or -6 during IFN signaling; these dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...

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.

In addition to the JAK-STAT pathway, IFNs can activate several other signaling cascades. Both type I and type II IFNs activate a member of the CRK family of adaptor protein
Adaptor protein
Signal transducing adaptor proteins are proteins which are accessory to main proteins in a signal transduction pathway. These proteins tend to lack any intrinsic enzymatic activity themselves but instead mediate specific protein–protein interactions that drive the formation of protein complexes...

s called CRKL
CRKL
Crk-like protein is a protein that in humans is encoded by the CRKL gene.CrkL together with Crk participates in the Reelin signaling cascade downstream of DAB1.-Interactions:...

, a nuclear adaptor for STAT5
STAT5
STAT5 refers to two highly related proteins, STAT5A and STAT5B, which are encoded by separate genes, but are 90% identical at the amino acid level....

 that also regulates signaling through the C3G
RAPGEF1
Rap guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the RAPGEF1 gene.-Interactions:RAPGEF1 has been shown to interact with BCAR1, Grb2, HCK, CRKL and CRK.-External links:* Info with links in the...

/Rap1
Rap1
Rap1 is a small GTPase, which are small cytosolic proteins that act like cellular switches and are vital for effective signal transduction. There are two isoforms of the Rap1 protein, each encoded by a separate gene, RAP1A and RAP1B...

 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
P70-S6 Kinase 1
Ribosomal protein S6 kinase beta-1 is an enzyme that in humans is encoded by the RPS6KB1 gene.-Interactions:P70-S6 Kinase 1 has been shown to interact with CSNK2B, EIF3B, COASY, KIAA1303, POLDIP3, Mammalian target of rapamycin, PPP2R2A, RBX1 and Ubiquitin C.-References:...

, an enzyme that increases protein synthesis and cell proliferation; phosphorylates of ribosomal protein s6
Ribosomal protein s6
Ribosomal protein S6 is a component of the 40S ribosomal subunit and is therefore thought to be involved in regulating translation. Once thought to regulate the translation of 5' terminal oligopyrimidine RNA, this has since been disproven...

, which is involved in protein synthesis; and phosphorylates a translational repressor protein called eukaryotic translation-initiation factor 4E-binding protein 1 (EIF4EBP1
EIF4EBP1
Eukaryotic translation initiation factor 4E-binding protein 1 is a protein that in humans is encoded by the EIF4EBP1 gene.-Interactions:EIF4EBP1 has been shown to interact with Mammalian target of rapamycin, EIF4E and KIAA1303.-Further reading:...

) in order to deactivate it.

Virus resistance to interferons


Many viruses have evolved mechanisms to resist interferon activity. 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. Viruses that inhibit IFN signaling include Japanese Encephalitis
Japanese Encephalitis
Japanese encephalitis —previously known as Japanese B encephalitis to distinguish it from von Economo's A encephalitis—is a disease caused by the mosquito-borne Japanese encephalitis virus. The Japanese encephalitis virus is a virus from the family Flaviviridae. Domestic pigs and wild birds are...

 Virus (JEV), dengue type 2 virus
Dengue virus
Dengue virus in one of four serotypes is the cause of dengue fever. It is a mosquito-borne single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus...

 (DEN-2) and viruses of the herpesvirus family, such as human cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...

 (HCMV) and Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus is one of seven currently known human cancer viruses, or oncoviruses. It is also the eighth human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses is HHV-8. Like other herpesviruses, its informal name is used...

  (KSHV or HHV8). Viral proteins proven to affect IFN signaling include EBV nuclear antigen 1 (EBNA1)
EBV nuclear antigen 1
Epstein-Barr nuclear antigen 1 is a multifunctional, dimeric viral protein associated with Epstein-Barr virus. It is the only viral protein of Epstein-Barr that is found in all EBV-related malignancies. It is important in establishing and maintaining the altered state that cells take when...

 and EBV nuclear antigen 2 (EBNA-2)
EBV nuclear antigen 2
EBV nuclear antigen 2 is a viral protein associated with Epstein-Barr virus.EBNA-2 is the main viral transactivator, switching transcription from the Wp promoters initially used after infection to the Cp promoter. Together with EBNA-3C, it also activates the LMP-1 promoter. It is known to bind...

 from Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...

, the large T antigen of Polyomavirus
Polyomavirus
Polyomavirus is the sole genus of viruses within the family Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross in 1953. Subsequently, many polyomaviruses have been found to infect birds and mammals...

, the E7 protein of Human papillomavirus
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...

 (HPV), and the B18R protein of vaccinia virus. Reducing IFN-α activity may prevent signaling via STAT1
STAT1
STAT1 is a member of the Signal Transducers and Activators of Transcription family of transcription factors. STAT1 is involved in upregulating genes due to a signal by either type I, type II or type III interferons...

, STAT2
STAT2
Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene.-Interactions:STAT2 has been shown to interact with MED14, CREB-binding protein, SMARCA4, STAT1, IFNAR2, IFNAR1 and ISGF3G.-Further reading:...

, or IRF9
ISGF3G
Interferon regulatory factor 9 is a protein that in humans is encoded by the IRF9 gene.-Interactions:ISGF3G has been shown to interact with STAT2 and STAT1....

  (as with JEV infection) or through the JAK-STAT pathway (as with DEN-2 infection). Several poxviruses 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
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...

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. The ability of interferon to induce protein production from interferon stimulated genes (ISGs) can also be affected. Production of protein kinase R
Protein kinase R
Protein kinase RNA-activated also known as protein kinase R , interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 is an enzyme that in humans is encoded by the EIF2AK2 gene.PKR protects against viral...

, for example, can be disrupted in cells infected with JEV or flavivirus
Flavivirus
Flavivirus is a genus of the family Flaviviridae. This genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, and several other viruses which may cause encephalitis....

es. Some viruses escape the anti-viral activities of interferons by gene (and thus protein) mutation. The H5N1
H5N1
Influenza A virus subtype H5N1, also known as "bird flu", A or simply H5N1, is a subtype of the influenza A virus which can cause illness in humans and many other animal species...

 influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...

 virus, also known as bird flu, has resistance to interferon and other anti-viral cytokines that is attributed to a single amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 change in its Non-Structural Protein 1 (NS1), although the precise mechanism of how this confers immunity is unclear.

Interferon therapy



Diseases


The immune effects of interferons have been exploited to treat several diseases. Agents that activate the immune system, such as small imidazoquinoline
Imidazoquinoline
Imidazoquinoline is a double cyclic organic molecule; its derivatives and compounds are often used for antiviral and antiallergic creams....

 molecules that activate TLR7, can induce IFN-α. Imidazoquinoline is the main ingredient of Aldara (Imiquimod) cream, a treatment approved in the United States by the Food and Drug Administration (FDA) for actinic keratosis
Actinic keratosis
Actinic keratosis is a premalignant condition of thick, scaly, or crusty patches of skin. It is more common in fair-skinned people. It is associated with those who are frequently exposed to the sun, as it is usually accompanied by solar damage...

, superficial basal cell carcinoma
Basal cell carcinoma
Basal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...

, papilloma
Papilloma
Papilloma refers to a benign epithelial tumor growing exophytically in finger-like fronds. In this context papilla refers to the projection created by the tumor, not a tumor on an already existing papilla . When used without context, it frequently refers to infections caused by human...

 and external genital warts. Synthetic IFNs are also made, and administered as antiviral, antiseptic
Antiseptic
Antiseptics are antimicrobial substances that are applied to living tissue/skin to reduce the possibility of infection, sepsis, or putrefaction...

 and anticarcinogen
Anticarcinogen
An anticarcinogen is any chemical which reduces the occurrence of cancers, reduces the severity of cancers that do occur, or acts against cancers that do occur, based on evidence from in vitro studies, animal models, epidemiological studies and/or clinical studies.Preventative anticarcinogens act...

ic drugs, and to treat some autoimmune diseases.

New research has shown that imiquimod's anti-proliferative effect is totally independent of immune system activation or function. Imiquimod exerts its effect by increasing levels of the opioid growth factor receptor (OGFr). Blocking OGFr function with siRNA
Sírna
Sírna Sáeglach , son of Dian mac Demal, son of Demal mac Rothechtaid, son of Rothechtaid mac Main, was, according to medieval Irish legend and historical tradition, a High King of Ireland...

 technology resulted in loss of any antiproliferative effect of imiquimod.

Interferon beta-1a
Interferon beta-1a
Interferon beta-1a is a drug in the interferon family used to treat multiple sclerosis . It is produced by mammalian cells, while Interferon beta-1b is produced in modified E. coli. Interferons have been shown to produce about a 18–38% reduction in the rate of MS relapses, and to slow the...

 and interferon beta-1b
Interferon beta-1b
Interferon beta-1b is a drug in the interferon family used to treat the relapsing-remitting and secondary-progressive forms of multiple sclerosis . It is approved for use after the first MS event...

 are used to treat and control multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...

, an autoimmune disorder. This treatment is effective for slowing disease progression and activity in relapsing-remitting multiple sclerosis and reducing attacks in secondary progressive multiple sclerosis.

Interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for many cancers. This treatment is most effective for treating hematological malignancy
Hematological malignancy
Hematological malignancies are the types of cancer that affect blood, bone marrow, and lymph nodes. As the three are intimately connected through the immune system, a disease affecting one of the three will often affect the others as well: although lymphoma is technically a disease of the lymph...

; leukemia and lymphomas including hairy cell leukemia
Hairy cell leukemia
Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a sub-type of chronic lymphoid leukemia...

, chronic myeloid leukemia, nodular lymphoma, cutaneous T-cell lymphoma. Patients with recurrent melanomas receive recombinant IFN-α2b. Type I IFNs have a therapeutic potential for the treatment of a wide variety of leukemias and solid tumors due to their antiproliferative and apoptotic effects, their anti-angiogenic effects and their ability to modulate an immune response specifically activating dendritic cells, cytolytic T cells and NK cells. Research in this area is receiving intensive investigation.

Both hepatitis B and hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...

 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 only be treated around 50% of time by the standard of care treatment of interferon-α/ribavirin. Given the treatment, biopsies  show reductions in liver damage and cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...

. 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
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...

.

Administered intranasally in very low doses, interferon is extensively used in Eastern Europe and Russia as a method to prevent and treat viral respiratory diseases such as cold
Common cold
The common cold is a viral infectious disease of the upper respiratory system, caused primarily by rhinoviruses and coronaviruses. Common symptoms include a cough, sore throat, runny nose, and fever...

 and flu. However, mechanisms of such action of interferon are not well understood; it is thought that doses must be larger by several orders of magnitude to have any effect on the virus. Although most Western scientists are skeptical of any claims of good efficacy, recent findings suggest that interferon applied to mucosa may act as an adjuvant
Immunologic adjuvant
In immunology, an adjuvant is an agent that may stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect in itself. The word “adjuvant” comes from the Latin word adiuvare, meaning to help or aid...

 against influenza virus, boosting the specific immune system response against the virus. A flu vaccine that uses interferon as adjuvant is currently under clinical trials in the US.

When used in the systemic therapy, IFNs are mostly administered by an intramuscular injection. The injection of IFNs in the muscle, in the vein, or under 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
Erythema
Erythema is redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin. It occurs with any skin injury, infection, or inflammation...

, pain and hardness on the spot of injection are also frequently observed. IFN therapy causes immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...

, in particular through neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...

 and can result in some infections manifesting in unusual ways.

Drug formulations

Pharmaceutical forms of interferons
Generic name Trade name
Interferon alpha 2a  Roferon A
Interferon alpha 2b
Interferon alfa-2b
Interferon alfa-2b is an antiviral drug originally discovered in the laboratory of Charles Weissmann at the University of Zurich, developed at Biogen, and ultimately marketed by Schering-Plough under the tradename Intron-A...

 
Intron A/Reliferon/Uniferon
Human leukocyte Interferon-alpha (HuIFN-alpha-Le) Multiferon
Multiferon
Interferon alfa is a natural interferon alpha which is obtained from the leukocyte fraction of human blood following induction with Sendai virus...

Interferon beta 1a
Interferon beta-1a
Interferon beta-1a is a drug in the interferon family used to treat multiple sclerosis . It is produced by mammalian cells, while Interferon beta-1b is produced in modified E. coli. Interferons have been shown to produce about a 18–38% reduction in the rate of MS relapses, and to slow the...

, liquid form
Rebif
Interferon beta 1a
Interferon beta-1a
Interferon beta-1a is a drug in the interferon family used to treat multiple sclerosis . It is produced by mammalian cells, while Interferon beta-1b is produced in modified E. coli. Interferons have been shown to produce about a 18–38% reduction in the rate of MS relapses, and to slow the...

, lyophilized
Avonex
Interferon beta 1a
Interferon beta-1a
Interferon beta-1a is a drug in the interferon family used to treat multiple sclerosis . It is produced by mammalian cells, while Interferon beta-1b is produced in modified E. coli. Interferons have been shown to produce about a 18–38% reduction in the rate of MS relapses, and to slow the...

, biogeneric (Iran)
Cinnovex
CinnoVex
CinnoVex is the trade name of recombinant Interferon beta 1-a, which is manufactured as biosimilar in Iran.- Description :An interferon-beta protein developed at the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Stuttgart, Germany, in collaboration with CinnaGen company,...

Interferon beta 1b
Interferon beta-1b
Interferon beta-1b is a drug in the interferon family used to treat the relapsing-remitting and secondary-progressive forms of multiple sclerosis . It is approved for use after the first MS event...

 
Betaseron / Betaferon
Interferon beta 1b
Interferon beta-1b
Interferon beta-1b is a drug in the interferon family used to treat the relapsing-remitting and secondary-progressive forms of multiple sclerosis . It is approved for use after the first MS event...

, biosimilar (Iran)
ZIFERON
PEGylated interferon alpha 2a  Pegasys
PEGylated interferon alpha 2a (Egypt) Reiferon Retard
PEGylated interferon alpha 2b
Peginterferon alfa-2b
Pegylated interferon alfa-2b is a treatment for hepatitis C developed by Schering-Plough, brand name is PegIntron.It was approved in January 2001....

 
PegIntron
PEGylated interferon alpha 2b
Peginterferon alfa-2b
Pegylated interferon alfa-2b is a treatment for hepatitis C developed by Schering-Plough, brand name is PegIntron.It was approved in January 2001....

 plus ribavirin
Ribavirin
Ribavirin is an anti-viral drug indicated for severe RSV infection , hepatitis C infection and other viral infections. Ribavirin is a prodrug, which when metabolised resembles purine RNA nucleotides...

 (Canada)
Pegetron


Several different types of interferon are now approved for use in humans. By March 10, 2009, MultiferonTM — known generically as human leukocyte interferon-alpha (HuIFN-alpha-Le) — was being used in 14 European countries. This drug was approved for treatment of patients with high risk (stage IIb-III) cutaneous melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...

, after 2 treatment cycles with dacarbazine
Dacarbazine
Dacarbazine is an antineoplastic chemotherapy drug used in the treatment of various cancers, among them malignant melanoma, Hodgkin lymphoma, sarcoma, and islet cell carcinoma of the pancreas.Dacarbazine is a member of the class of alkylating agents, which destroy cancer cells by adding an alkyl...

, following a clinical trial performed in Germany.

In January 2001, the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (FDA) approved the use of PEGylated interferon-alpha in the USA; in this formulation, polyethylene glycol
Polyethylene glycol
Polyethylene glycol is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide or polyoxyethylene , depending on its molecular weight, and under the tradename Carbowax.-Available forms:PEG, PEO, or POE refers to an...

 is added to make the interferon last longer in the body. Initially used for production of PEGylated interferon-alpha-2b
Peginterferon alfa-2b
Pegylated interferon alfa-2b is a treatment for hepatitis C developed by Schering-Plough, brand name is PegIntron.It was approved in January 2001....

 (Pegintron), approval for PEGylated interferon-alpha-2a (Pegasys) followed in October 2002. These PEGylated drugs are injected once weekly, rather than administering three times per week, as is necessary for conventional interferon-alpha. When used with the antiviral
Antiviral
Antiviral may refer to:*Antiviral drug*Antiviral protein*Antivirus software*Antiviral Therapy, an academic journal...

 drug ribavirin
Ribavirin
Ribavirin is an anti-viral drug indicated for severe RSV infection , hepatitis C infection and other viral infections. Ribavirin is a prodrug, which when metabolised resembles purine RNA nucleotides...

, PEGylated interferon is effective in treatment of hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...

; at least 75% 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).

History


During research to produce a more efficient vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

 for smallpox
Smallpox
Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning "spotted", or varus, meaning "pimple"...

, Yasu-ichi Nagano and Yasuhiko Kojima — two Japanese virologists
Virology
Virology is the study of viruses and virus-like agents: their structure, classification and evolution, their ways to infect and exploit cells for virus reproduction, the diseases they cause, the techniques to isolate and culture them, and their use in research and therapy...

 working at the Institute for Infectious Diseases at the University of Tokyo
University of Tokyo
, abbreviated as , is a major research university located in Tokyo, Japan. The University has 10 faculties with a total of around 30,000 students, 2,100 of whom are foreign. Its five campuses are in Hongō, Komaba, Kashiwa, Shirokane and Nakano. It is considered to be the most prestigious university...

 — noticed inhibition of viral growth in an area of rabbit-skin or testis previously 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 homogenate
Homogenization (biology)
Homogenization is a process that involves breaking apart cells — releasing organelles and cytoplasm.When the purpose is to extract organelles, it is frequently done in two steps; first using a blender to break the tissue up, and then with an ultrasonic or mechanical tissue disruptor. The...

s. In 1954, these findings were published in a French journal now known as “Journal de la Société de Biologie”. After Nagano and Kojima separated the viral inhibitory factor from the viral particles using Ultracentrifugation, they confirmed its antiviral activity lasted 1–4 days and did not result from antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 production; their findings were published in 1958. Nagano’s work was never fully appreciated in the scientific community; possibly because it was printed in French
French language
French is a Romance language spoken as a first language in France, the Romandy region in Switzerland, Wallonia and Brussels in Belgium, Monaco, the regions of Quebec and Acadia in Canada, and by various communities elsewhere. Second-language speakers of French are distributed throughout many parts...

, but also because his in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

system was perhaps too complex to provide clear results in the characterisation and purification of interferon.

Meanwhile, the British virologist Alick Isaacs
Alick Isaacs
Alick Isaacs was a British virologist. He is best remembered for his work on interferon, having been Head of the Laboratory for Research on Interferon, National Institute for Medical Research, 1964–7....

 and the Swiss researcher Jean Lindenmann, at the National Institute for Medical Research
National Institute for Medical Research
The National Institute for Medical Research, commonly abbreviated to NIMR, is a medical research facility situated in Mill Hill, on the outskirts of London, England. It is mainly funded by the Medical Research Council, or MRC, and is its largest establishment and the only one designated as an...

 in London, noticed an interference effect caused by heat-inactivated influenza virus on the growth of live influenza virus in chicken egg chorioallantoic membrane
Chorioallantoic membrane
The chorioallantoic membrane — also called the chorioallantois or abbreviated to CAM — is a vascular membrane found in eggs of some amniotes, such as birds and reptiles. It is formed by the fusion of the mesodermal layers of two developmental structures: the allantois and the chorion...

. They published their results, attaining wide recognition, in 1957; in this paper they coined the term ‘interferon’, and today that specific interfering agent is known as a ‘Type I interferon’. The majority of the credit for discovery of the interferon goes to Isaacs and Lindenmann, with whom there is no record of Nagano ever having made personal contact.
The purification of interferons did not occur until 1978. A series of publications from the laboratories of Sidney Pestka
Sidney Pestka
Sidney Pestka is an American biochemist and geneticist. He is sometimes referred to as the "father of interferon" for his groundbreaking work developing the interferons as treatments for major diseases such as hepatitis, multiple sclerosis, and cancer...

 and Alan Waldman between 1978 and 1981, describe the purification of the type I interferons IFN-α and IFN-β. By the early 1980s, the genes for these interferons were cloned allowing — for the first time — definitive proof that interferons really were responsible for interfering with viral replication. Gene cloning also confirmed that IFN-α was encoded by, not one gene, but a family of related genes. The type II IFN (IFN-γ) gene was also isolated around this time.

Interferon was scarce and expensive until 1980 when the interferon gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

 was inserted into bacteria using recombinant DNA technology, allowing mass cultivation and purification from bacterial cultures or derived from yeast (e.g. Reiferon Retard is the first yeast derived interferon-alpha 2a).

After his work on the discovery of interferon, Dr. Kojima conducted extensive research on the development of a natural substance that could stimulate the human body's production of interferon. After 40 years he developed Kampo Formula EH0202 (tradename: NutriFeron) and sold the worldwide rights to Shaklee Corporation of the USA. To date, EH0202 is the only known natural formula to successfully stimulate the human body to produce interferon. Shaklee funded several research projects with Kampo Formula EH0202 and found that it was effective in the treatment of chronic hepatitis C , that it stimulated the immune system and it’s production of natural interferon, , and that it also reduced menopause-related symptoms. NutriFeron by Shaklee is the only herbal product available that has documented the ability to stimulate natural interferon production.

Human interferons

  • IFNA1
    IFNA1
    Interferon alpha-1/13 is a protein that in humans is encoded by the IFNA1 gene.-Further reading:...

  • IFNA2
    IFNA2
    Interferon alpha-2 is a protein that in humans is encoded by the IFNA2 gene.-Further reading:...

  • IFNA4
    IFNA4
    Interferon alpha-4 is a protein that in humans is encoded by the IFNA4 gene.-Further reading:...

  • IFNA5
    IFNA5
    Interferon alpha-5 is a protein that in humans is encoded by the IFNA5 gene.-Further reading:...

  • IFNA6
    IFNA6
    Interferon alpha-6 is a protein that in humans is encoded by the IFNA6 gene.-Further reading:...

  • IFNA7
    IFNA7
    Interferon alpha-7 is a protein that in humans is encoded by the IFNA7 gene.-Further reading:...

  • IFNA8
    IFNA8
    Interferon alpha-8 is a protein that in humans is encoded by the IFNA8 gene.-Further reading:...

  • IFNA10
    IFNA10
    Interferon alpha-10 is a protein that in humans is encoded by the IFNA10 gene.-Further reading:...

  • IFNA13
    IFNA13
    Interferon alpha-1/13, also known as IFN-alpha-1/13, is a protein that in humans is encoded by the IFNA1 and IFNA13 genes.-Further reading:IFNA13 is an interferon gene....

  • IFNA14
    IFNA14
    Interferon alpha-14 is a protein that in humans is encoded by the IFNA14 gene.-Further reading:...

  • IFNA16
    IFNA16
    Interferon alpha-16, also known as IFN-alpha-16, is a protein that in humans is encoded by theIFNA16 gene....

  • IFNA17
    IFNA17
    Interferon alpha-17 is a protein that in humans is encoded by the IFNA17 gene.-Further reading:...

  • IFNA21
    IFNA21
    Interferon alpha-21 is a protein that in humans is encoded by the IFNA21 gene.-Further reading:...

  • IFNB1
    IFNB1
    Interferon beta is a protein that in humans is encoded by the IFNB1 gene.-Further reading:...

  • IFNW
  • IFNE1
  • IFNK
    IFNK
    Interferon kappa, also known as IFN-kappa, is a protein that in humans is encoded by the IFNK gene.- Function :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...


See also

  • Immunotherapy
    Immunotherapy
    Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...

  • Immunosuppression
    Immunosuppression
    Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...

  • Immunosuppressive drug
    Immunosuppressive drug
    Immunosuppressive drugs or immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to:...

  • ATC code L03#L03AB Interferons
  • Interferon Consensus Sequence-binding protein