Interferon type I
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.[1]
Not to be confused with Interferon type II.
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[edit]
IFN-α and IFN-β are secreted by many cell types including lymphocytes (NK cells, B-cells and T-cells), macrophages, fibroblasts, endothelial cells, osteoblasts and others. They stimulate both macrophages and NK cells to elicit an anti-viral response, involving IRF3/IRF7 antiviral pathways,[4] 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 leukocytes at the site of viral infection or tumors.
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).
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]
Interferon type I in cancer[edit]
Therapeutics[edit]
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, renal cell carcinoma, Kaposi's sarcoma, multiple myeloma, follicular and non-Hodgkin lymphoma, and chronic myelogenous leukemia. Human IFNβ (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[edit]
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 and decreased overall survival in cancer.[1]
Use of Interferon type I in therapeutics[edit]
In cancer[edit]
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, renal cell carcinoma, Kaposi's sarcoma, multiple myeloma, follicular and non-Hodgkin lymphoma, and chronic myelogenous leukemia. Human IFNβ (Feron, Toray ltd.) has also been approved in Japan to treat glioblastoma, medulloblastoma, astrocytoma, and melanoma.[1]
Side effects of type I interferon therapy[edit]
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[edit]
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[edit]
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.[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]