Interferon-alpha beta receptor
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The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cytoband over approximately 400 kb including coding genes for IFNα (''IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17'' and ''IFNA21''), IFNω (''IFNW1''), IFNɛ (''IFNE''), IFNк (''IFNK'') and IFNβ (''IFNB1''), plus 11 IFN pseudogenes. Interferons bind to
interferon receptor Type II cytokine receptors, also commonly known as class II cytokine receptors, are transmembrane proteins that are expressed on the surface of certain cells. They bind and respond to a select group of cytokines including interferon type I, i ...
s. All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor (
IFNAR The interferon-α/β receptor (IFNAR) is a virtually ubiquitous membrane receptor which binds endogenous type I interferon (IFN) cytokines. Endogenous human type I IFNs include many subtypes, such as interferons-α, -β, -ε, -κ, -ω, and -ζ. ...
) that consists of
IFNAR1 Interferon-alpha/beta receptor alpha chain is a protein that in humans is encoded by the ''IFNAR1'' gene. Function The protein encoded by this gene is a type I membrane protein that forms one of the two chains of a receptor for type I interfer ...
and IFNAR2 chains. Type I IFNs are found in all mammals, and homologous (similar) molecules have been found in birds, reptiles, amphibians and fish species.


Sources and functions

IFN-α and IFN-β are secreted by many cell types including
lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...
( NK cells,
B-cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...
s and T-cells), macrophages, fibroblasts, endothelial cells, osteoblasts and others. They stimulate both
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s and NK cells to elicit an anti-viral response, involving IRF3/IRF7 antiviral pathways, and are also active against tumors. Plasmacytoid dendritic cells have been identified as being the most potent producers of type I IFNs in response to antigen, and have thus been coined natural IFN producing cells. IFN-ω is released by
leukocyte White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
s at the site of viral infection or tumors. IFN-α acts as a
pyrogenic Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using valu ...
factor by altering the activity of thermosensitive neurons in the hypothalamus thus causing fever. It does this by binding to opioid receptors and eliciting the release of prostaglandin-E2 (PGE2). A similar mechanism is used by IFN-α to reduce pain; IFN-α interacts with the μ-opioid receptor to act as an
analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
. In mice, IFN-β inhibits immune cell production of growth factors, thereby slowing tumor growth, and inhibits other cells from producing vessel producing growth factors, thereby blocking tumor angiogenesis and hindering the tumour from connecting into the blood vessel system. * In both mice and human, negative regulation of type I interferon signaling is known to be important. Few endogenous regulators have been found to elicit this important regulatory function, such as SOCS1 and Aryl Hydrocarbon Receptor Interacting Protein (AIP).


Mammalian types

The mammalian types are designated IFN-α (alpha), IFN-β (beta), IFN-κ (kappa), IFN-δ (delta), IFN-ε (epsilon), IFN-τ (tau), IFN-ω (omega), and IFN-ζ (zeta, also known as limitin). Of these types, IFN-α, IFN -ω, and IFN-τ can work across species.


IFN-α

The IFN-α proteins are produced mainly by plasmacytoid dendritic cells (pDCs). They are mainly involved in innate immunity against viral infection. The genes responsible for their synthesis come in 13 subtypes that are called
IFNA1 Interferon alpha-1 is a protein that in humans is encoded by the ''IFNA1'' gene. Leukocyte interferon is produced predominantly by B cell, B lymphocytes. Immune interferon (Interferon gamma, IFN-gamma; MIM 147570) is produced by mitogen- or antig ...
,
IFNA2 Interferon alpha-2 is a protein that in humans is encoded by the ''IFNA2'' gene. Protein family Human interferon alpha-2 (IFNα2) is a cytokine belonging to the family of type I IFNs. IFNα2 is a protein secreted by cells infected by a virus ...
,
IFNA4 Interferon alpha-4 is a protein that in humans is encoded by the ''IFNA4'' gene. References Further reading

* * * * * * * * * * {{gene-9-stub ...
,
IFNA5 Interferon alpha-5 is a protein that in humans is encoded by the ''IFNA5'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birt ...
,
IFNA6 Interferon alpha-6 is a protein that in humans is encoded by the ''IFNA6'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birt ...
,
IFNA7 Interferon alpha-7 is a protein that in humans is encoded by the ''IFNA7'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''bir ...
,
IFNA8 Interferon alpha-8 is a protein that in humans is encoded by the ''IFNA8'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birt ...
,
IFNA10 Interferon alpha-10 is a protein that in humans is encoded by the ''IFNA10'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''bi ...
, IFNA13,
IFNA14 Interferon alpha-14 is a protein that in humans is encoded by the ''IFNA14'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''b ...
,
IFNA16 Interferon alpha-16, also known as IFN-alpha-16, is a protein that in humans is encoded by the''IFNA16'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." m ...
,
IFNA17 Interferon alpha-17 is a protein that in humans is encoded by the ''IFNA17'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''b ...
, 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 Interferon alfa (INN) or HuIFN-alpha-Le, trade name Multiferon, is a pharmaceutical drug composed of natural interferon alpha (IFN-α), obtained from the leukocyte fraction of human blood following induction with Sendai virus. Interferon alfa conta ...
. The recombinant type is
interferon alfacon-1 Interferon alfacon-1 is a recombinant synthetic type I interferon used for the treatment of hairy cell leukemia, malignant melanoma and AIDS-related Kaposi's sarcoma Kaposi's sarcoma (KS) is a type of cancer that can form masses in the skin, ...
. The pegylated types are
pegylated interferon alfa-2a Pegylated interferon alfa-2a, sold under the brand name Pegasys among others, is medication used to treat hepatitis C and hepatitis B. For hepatitis C it is typically used together with ribavirin and cure rates are between 24 and 92%. For hepatit ...
and
pegylated interferon alfa-2b Pegylated interferon alfa-2b is a drug used to treat melanoma, as an adjuvant therapy to surgery. Also used to treat hepatitis C (typically, in combination with ribavarin), it is no longer recommended due to poor efficacy and adverse side-effec ...
.
Recombinant feline interferon omega Recombinant feline interferon omega (RFeIFN-ω), sold under the brand name Virbagen Omega among others, is a recombinant version of a cat interferon alpha. It is used to treat a range of viral diseases in cats and dogs, including canine parvoviru ...
is a form of cat IFN-α (not ω) for veterinary use.


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 Interferon beta is a protein that in humans is encoded by the ''IFNB1'' gene. The natural and recombinant protein Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloni ...
) and IFN-β3 ( IFNB3) (a gene designated IFN-β2 is actually IL-6). IFN-β1 is used as a treatment for
multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
as it reduces the relapse rate. IFN-β1 is not an appropriate treatment for patients with progressive, non-relapsing forms of multiple sclerosis., which cites * *


IFN-ε, -κ, -τ, -δ and -ζ

IFN-ε, -κ, -τ, and -ζ appear, at this time, to come in a single isoform in humans, '' IFNK''. Only ruminants encode IFN-τ, a variant of IFN-ω. So far, IFN-ζ is only found in mice, while a structural homolog, IFN-δ is found in a diverse array of non-primate and non-rodent placental mammals. Most but not all placental mammals encode functional IFN-ε and IFN-κ genes.


IFN-ω

IFN-ω, although having only one functional form described to date (''
IFNW1 Interferon omega-1 is a protein that in humans is encoded by the ''IFNW1'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''bir ...
''), has several
pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by DNA duplication or indirectly by Reverse transcriptase, reverse transcription of an mRNA trans ...
s: , , , , , , and in humans. Many non-primate placental mammals express multiple IFN-ω subtypes.


IFN-ν

This subtype of type I IFN was recently described as a pseudogene in human, but potentially functional in the domestic cat genome. In all other genomes of non-feline placental mammals, IFN-ν is a pseudogene; in some species, the pseudogene is well preserved, while in others, it is badly mutilated or is undetectable. Moreover, in the cat genome, the IFN-ν promoter is deleteriously mutated. It is likely that the IFN-ν gene family was rendered useless prior to mammalian diversification. Its presence on the edge of the type I IFN locus in mammals may have shielded it from obliteration, allowing its detection.


Interferon type I in cancer


Therapeutics

From the 1980s onward, members of type-I IFN family have been the standard care as immunotherapeutic agents in cancer therapy. In particular, IFNα has been approved by the US Food and Drug Administration (FDA) for cancer. To date, pharmaceutical companies produce several types of recombinant and pegylated IFNα for clinical use; e.g., IFNα2a ( Roferon-A, Roche), IFNα2b ( Intron-A, Schering-Plough) and pegylated IFNα2b (Sylatron, Schering Corporation) for treatment of hairy cell leukemia,
melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
, renal cell carcinoma, Kaposi's sarcoma,
multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
, follicular and non-Hodgkin lymphoma, and
chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulat ...
. Human IFNβ (
Feron Fafnir Falcon Sam Wilson Joaquin Torres Falcona Falligar the Behemoth Falligar the Behemoth, also known simply as Falligar, is a fictional deity who makes a single appearance in '' Thor: God of Thunder'' #3 (December 2012), as one of the ...
, Toray ltd.) has also been approved in Japan to treat glioblastoma, medulloblastoma, astrocytoma, and
melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
br>


Copy number alteration of the interferon gene cluster in cancer

A large individual patient data meta-analysis using 9937 patients obtained from cBioportal indicates that copy number alteration of the IFN gene cluster is prevalent among 24 cancer types. Notably deletion of this cluster is significantly associated with increased mortality in many cancer types particularly uterus, kidney, and brain cancers. The Cancer Genome Atlas PanCancer analysis also showed that copy number alteration of the IFN gene cluster is significantly associated with decreased overall survival. For instance, the overall survival of patients with brain glioma reduced from 93 months (diploidy) to 24 months. In conclusion, the copy number alteration of the IFN gene cluster is associated with increased
mortality Mortality is the state of being mortal, or susceptible to death; the opposite of immortality. Mortality may also refer to: * Fish mortality, a parameter used in fisheries population dynamics to account for the loss of fish in a fish stock throug ...
and decreased overall survival in cancer.


Non-mammalian types

Avian type I IFNs have been characterized and preliminarily assigned to subtypes (IFN I, IFN II, and IFN III), but their classification into subtypes should await a more extensive characterization of avian genomes. Functional lizard type I IFNs can be found in lizard genome databases. Turtle type I IFNs have been purified (references from 1970s needed). They resemble mammalian homologs. The existence of amphibian type I IFNs have been inferred by the discovery of the genes encoding their receptor chains. They have not yet been purified, or their genes cloned. Piscine (bony fish) type I IFN has been cloned first in zebrafish. and then in many other teleost species including salmon and mandarin fish. With few exceptions, and in stark contrast to avian and especially mammalian IFNs, they are present as single genes (multiple genes are however seen in polyploid fish genomes, possibly arising from whole-genome duplication). Unlike amniote IFN genes, piscine type I IFN genes contain introns, in similar positions as do their orthologs, certain interleukins. Despite this important difference, based on their 3-D structure these piscine IFNs have been assigned as Type I IFNs. While in mammalian species all Type I IFNs bind to a single receptor complex, the different groups of piscine type I IFNs bind to different receptor complexes. Until now several type I IFNs (IFNa, b, c, d, e, f and h) has been identified in teleost fish with as low as only one subtype in green pufferfish and as many as six subtypes in salmon with an addition of recently identified novel subtype, IFNh in mandarin fish.


References


External links

* * {{DEFAULTSORT:Interferon Type I Cytokines Antiviral drugs Immunostimulants