Interferon type I

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(Redirected from
Interferon beta
)
Interferon Type I (α/β/δ...)
SCOP2
1au1 / SCOPe / SUPFAM
CDDcd00095
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1b5l :24-187 1ovi :24-185 2hie :24-186

1itf :24-186 1au1B:22-187 2hif :24-182

1wu3I:22-182

The type-I interferons (IFN) are

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.[1]

Interferons bind to

interferon receptors. All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor (IFNAR) that consists of IFNAR1 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.[2][3]

Sources and functions

IFN-α and IFN-β are secreted by many cell types including

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.[citation needed
]

IFN-ω is released by

leukocytes at the site of viral infection or tumors.[citation needed
]

IFN-α acts as a

pyrogenic 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).[citation needed
]

A similar mechanism is used by IFN-α to reduce pain; IFN-α interacts with the μ-opioid receptor to act as an analgesic.[5]

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.[6]

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).[7]

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).[8][9] Of these types, IFN-α, IFN -ω, and IFN-τ can work across species.[10]

IFN-α

The IFN-α proteins are produced mainly by

. These genes are found together in a cluster on chromosome 9.

IFN-α is also made synthetically as

pegylated interferon alfa-2b
.

Recombinant feline interferon omega is a form of cat IFN-α (not ω) for veterinary use.[10]

IFN-β

The IFN-β proteins are produced in large quantities by

IL-6
).

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.[citation needed].

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.

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.[citation needed]

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

Feron, Toray ltd.) has also been approved in Japan to treat glioblastoma, medulloblastoma, astrocytoma, and melanoma.[1]

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

Use of Interferon type I in therapeutics

In cancer

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

Feron, Toray ltd.) has also been approved in Japan to treat glioblastoma, medulloblastoma, astrocytoma, and melanoma. [1]

Combinational therapy with PD-1/PD-L1 inhibitors

By combining

activation of T cells within the tumor microenvironment, the development of memory T cells, and prolonged patient survival. [12]

In viral infection

Due to their strong antiviral properties, recombinant type 1 IFNs can be used for the treatment for persistent viral infection. Pegylated IFN-α is the current standard of care when it comes to chronic Hepatitis B and C infection. [13]

In multiple sclerosis

Currently, there are four FDA approved variants of IFN-β1 used as a treatment for relapsing multiple sclerosis.[14] IFN-β1 is not an appropriate treatment for patients with progressive, non-relapsing forms of multiple sclerosis.[15] Whilst the mechanism of action is not completely understood, the use of IFN-β1 has been found to reduce brain lesions, increase the expression of anti-inflammatory cytokines and reduce T cell infiltration into the brain. [16][17]

Side effects of type I interferon therapy

One of the major limiting factors in the efficacy of type I interferon therapy are the high rates of side effects. Between 15% - 40% of people undergoing type 1 IFN treatment develop major depressive disorders.[18] Less commonly, interferon treatment has also been associated with anxiety, lethargy, psychosis and parkinsonism.[19] Mood disorders associated with IFN therapy can be reversed by discontinuation of treatment, and IFN therapy related depression is effectively treated with the selective serotonin reuptake inhibitor class of antidepressants. [20]

Interferonopathies

Interferonopathies are a class of hereditary auto-inflammatory and autoimmune diseases characterised by upregulated type 1 interferon and downstream interferon stimulated genes. The symptoms of these diseases fall in a wide clinical spectrum, and often resemble those of viral infections acquired while the child is in utero, although lacking any infectious origin.[21] The aetiology is largely still unknown, but the most common genetic mutations are associated with nucleic acid regulation, leading most researchers to suggest these arise from the failure of antiviral systems to differentiate between host and viral DNA and RNA.[22]

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.[citation needed]

Functional lizard type I IFNs can be found in lizard genome databases.[citation needed]

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.[23][24] and then in many other teleost species including salmon and mandarin fish.[25][26] 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.[27] 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.[28] 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.[25][26]

References

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  13. ^ Foster GR. Past, present, and future hepatitis C treatments. Semin Liver Dis 2004;24:97–104. [PubMed:15346252]
  14. ^ Filipi M, Jack S. Interferons in the Treatment of Multiple Sclerosis: A Clinical Efficacy, Safety, and Tolerability Update. Int J MS Care. 2020;22(4):165-172. doi:10.7224/1537-2073.2018-063
  15. ABIM Foundation
    , American Academy of Neurology, retrieved August 1, 2013, which cites
  16. ^ Kieseier  BC.  The  mechanism  of  action  of  interferon-beta  in  relapsing  multiple sclerosis. CNS Drugs. 2011;25:491-502
  17. ^ Kasper  LH,  Reder  AT.  Immunomodulatory  activity  of  interferon-beta.  Ann Clin Transl Neurol. 2014;1:622-631.
  18. ^ Lotrich FE. Major depression during interferon-alpha treatment: vulnerability and prevention. Dialogues Clin Neurosci. 2009;11(4):417-425. doi:10.31887/DCNS.2009.11.4/felotrich
  19. ^ Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19(2):105-123. doi:10.2165/00023210-200519020-00002
  20. ^ Pinto EF, Andrade C. Interferon-Related Depression: A Primer on Mechanisms, Treatment, and Prevention of a Common Clinical Problem. Curr Neuropharmacol. 2016;14(7):743-748. doi:10.2174/1570159x14666160106155129
  21. ^ d'Angelo DM, Di Filippo P, Breda L and Chiarelli F (2021) Type I Interferonopathies in Children: An Overview. Front. Pediatr. 9:631329. doi: 10.3389/fped.2021.631329
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External links