Interferon alpha-1

Last updated
IFNA1
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases IFNA1 , IFL, IFN, IFN-ALPHA, IFN-alphaD, IFNA13, IFNA@, Interferon, alpha 1, interferon alpha 1, leIF D
External IDs OMIM: 147660 HomoloGene: 136811 GeneCards: IFNA1
Orthologs
SpeciesHumanMouse
Entrez

3439

n/a

Ensembl

ENSG00000197919

n/a

UniProt

P01562

n/a

RefSeq (mRNA)

NM_024013

n/a

RefSeq (protein)

NP_076918

n/a

Location (UCSC) Chr 9: 21.44 – 21.44 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Interferon alpha-1 is a protein that in humans is encoded by the IFNA1 gene. [3] [4]

Contents

Leukocyte interferon is produced predominantly by B lymphocytes. Immune interferon (IFN-gamma; MIM 147570) is produced by mitogen- or antigen-stimulated T lymphocytes.[supplied by OMIM] [4]

The type I interferon gene family

The interferons (IFN)s are a family of cytokines with potent antiviral, antiproliferative and immunomodulatory properties. [5] [6] IFNs were originally discovered as molecules that could reduce the ability of a normal virus to infect cells, a process called viral 'interference'. [7] [8] IFNs have been classified into two major types of IFNs, type I and type II, based on their interactions to a specific cell surface receptor. [6] [9] In recent years, a novel class of cytokines with IFN-like activities has been described and designated as type III IFNs (IFN-λ1-3). [10] In humans, there are 13 different IFN-alpha genes, designated as IFN-α1, -α2, - α4, - α5, - α6, - α7, - α8, - α10, - α13, - α14, - α16, - α17 and - α21, and one each of the IFN beta (IFNB), IFN-Epsilon, IFN-Kappa and IFN-Omega genes. [11] The human IFNA gene family shares 70-80% amino acid sequence homology, and about 35% identity with IFNB. [12] The high degree of amino-acid sequence similarity within the IFNA genes suggests a common ancestor gene. It seems likely that the IFNA gene cluster has been generated by gene conversion or recent duplication events. There are 12 functional human IFNA gene products. All of these IFN-α proteins exhibit high homology in their primary, secondary, and tertiary structures. [9] IFNA and IFNB are produced by a wide range of cells such as macrophages, fibroblasts and endothelial cells, but plasmacytoid dendritic cells (pDCs) are considered the main producers of IFNA in response to RNA or DNA viruses or nucleic acid-containing immune complexes. [13]

Type I IFN Signaling

The type I IFNs bind to the interferon alpha receptor (IFNAR), which consists of two subunits, IFNAR1 (α-subunit) and IFNAR2 (β-subunit). Two cytoplasmic tyrosine kinases provide downstream signaling after type I IFN binds to the IFNAR receptor, Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2). The biological effects of IFNs are mediated through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. STAT1 and STAT2 are activated by these tyrosine kinases, and STAT1 and STAT2 mediate the antiviral and inflammatory effects of IFN-α/IFN-β. [14] STAT1 and STAT2 form a complex with IFN-regulatory factor 9 (IRF) forming the transcription factor complex ISGF3, [15] which then translocates to the nucleus and binds to IFN-stimulated response elements (ISREs) in the promoters of IFN-regulated genes (IRGs). In addition, canonical type I IFN signalling may activate STAT1 homodimers that bind to interferon-gamma-activating factor (GAF), which also translocates to the nucleus and activates transcription of IFN-stimulated genes. [16]

Inducers of type I IFN

The virus-induced expression of IFNA/IFNB genes is primarily controlled at the gene transcription level, by the interferon regulatory factors (IRFs) and IFN-stimulated genes. [17] Viruses and immune complexes (ICs) containing nucleic acids can access intracellular TLRs (TLR3, TLR7/8 and TLR9) after binding to Fc receptors and induce IFN-α production by activation of the IRFs. [17] [18] Signaling through TLRs can broadly be categorized into two pathways the MyD88 and the Trip-dependent pathway. All TLRs except TLR3 signal through the MyD88-dependent pathway. Only TLR3 and TLR4 signal through the TRIF-dependent pathway. [18] The MyD88-dependent pathway recruits several effector molecules such as IRAK1/4 and tumor necrosis factor receptor-associated factor 6 (TRAF6). [19] These molecules are linked to at least three major downstream pathways: the NF-κB pathway, the pathway involving mitogen-activated protein kinases (MAPKs) and IRF pathways, depending on the stimulus and the responding cell types activation of these pathways results in transcription of various cytokines including IFN-α/β. [18] Signaling via cytosolic viral sensors can also activate similar pathways and result in transcription of IFN-α/β. [20]

Disease relevance

Emerging evidence suggests that abnormal IFN production contributes to immune dysfunction and mediates tissue inflammation and organ damage in a number of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), idiopathic inflammatory myopathies (IIM), Sjogren's syndrome (SS) and multiple sclerosis (MS). Increased serum IFN-α and IFN-α-induced gene expression are frequently observed in patients with SLE, and many of SLE clinical manifestations such as fever, fatigue and leukopenia are similar to those observed in patients with influenza or as a side effect of IFN-therapy, suggesting that type I IFNs are important in the molecular pathogenesis of SLE. [21] [22] [23] [24] A heritable pattern of high circulating type I IFN has been observed in SLE families, suggesting that high IFN is a heritable risk factor for SLE. [25] Furthermore, patients with non-autoimmune diseases treated with IFN-α can develop a “lupus-like” syndrome, including antinuclear antibodies (ANA) and anti-double stranded DNA (ds-DNA) which usually resolve after IFN-α therapy discontinuation. [24] As noted above, IRFs are proteins which regulate transcription of IFNs. Genetic variations in the IRF genes have been associated with risk of developing SLE, and these genetic variations have also been linked to increased IFN-α production and with SLE-associated autoantibody formation. [26] [27] Several observations suggest that type I IFN is involved in the pathogenesis of inflammatory myopathies. Patients with dermatomyositis and polymyositis have increased IFN serum levels which in some studies correlate with disease activity or myositis-specific autoantibodies. [28] [29] [30] [31] Also, studies have suggested a genetic or heritable component to the high type I IFN observed in myositis patients, similar to SLE. [32] [33] Multiple sclerosis (MS) is a disorder of the central nervous system characterized by inflammation, demyelination and neurodegeneration with presumed autoimmune origin. Whereas type I IFNs are thought to induce some autoimmune conditions such as SLE as noted above, MS is effectively treated by administering recombinant human IFN-β. MS patients have lower levels of circulating type I interferon compared to patients with other autoimmune diseases. [34] [35] However, a number of patients with relapsing-remitting MS have a high IFN signature as well as more clinical and MRI attacks before therapy and these patients often do not response to IFN-β therapy. [36] Neuromyelitis optica, another autoimmune disorder similar to MS which does not respond to IFN therapy, is associated with higher baseline circulating IFN levels. [37]

Current and future therapeutic options

Several IFN-blocking strategies are currently being evaluated in clinical trials. For instance, a phase I clinical trial of the anti-IFN-α monoclonal antibody MEDI-545 in SLE patients suggested possible disease activity improvement in SLE patients. [38] Another phase I clinical trial has reported a dose-dependent inhibition of IFN-α/β-inducible genes in both peripheral blood and skin biopsies in SLE patients treated with anti-IFN monoclonal antibody therapy. [39] Also, some studies suggest that type I IFN in circulation may be useful to predict response to immunotherapy in RA. [40] [41]

Notes

Related Research Articles

<span class="mw-page-title-main">Interferon</span> Signaling proteins released by host cells in response to the presence of pathogens

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

<span class="mw-page-title-main">Interferon regulatory factors</span> Protein family

Interferon regulatory factors (IRF) are proteins which regulate transcription of interferons. Interferon regulatory factors contain a conserved N-terminal region of about 120 amino acids, which folds into a structure that binds specifically to the IRF-element (IRF-E) motifs, which is located upstream of the interferon genes. Some viruses have evolved defense mechanisms that regulate and interfere with IRF functions to escape the host immune system. For instance, the remaining parts of the interferon regulatory factor sequence vary depending on the precise function of the protein. The Kaposi sarcoma herpesvirus, KSHV, is a cancer virus that encodes four different IRF-like genes; including vIRF1, which is a transforming oncoprotein that inhibits type 1 interferon activity. In addition, the expression of IRF genes is under epigenetic regulation by promoter DNA methylation.

Plasmacytoid dendritic cells (pDCs) are a rare type of immune cell that are known to secrete large quantities of type 1 interferon (IFNs) in response to a viral infection. They circulate in the blood and are found in peripheral lymphoid organs. They develop from bone marrow hematopoietic stem cells and constitute < 0.4% of peripheral blood mononuclear cells (PBMC). Other than conducting antiviral mechanisms, pDCs are considered to be key in linking the innate and adaptive immune systems. However, pDCs are also responsible for participating in and exacerbating certain autoimmune diseases like lupus. pDCs that undergo malignant transformation cause a rare hematologic disorder, blastic plasmacytoid dendritic cell neoplasm.

<span class="mw-page-title-main">Integrin alpha M</span> Mammalian protein found in Homo sapiens

Integrin alpha M (ITGAM) is one protein subunit that forms heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3). ITGAM is also known as CR3A, and cluster of differentiation molecule 11B (CD11B). The second chain of αMβ2 is the common integrin β2 subunit known as CD18, and integrin αMβ2 thus belongs to the β2 subfamily integrins.

<span class="mw-page-title-main">Interleukin 29</span> Protein-coding gene in the species Homo sapiens

Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.

<span class="mw-page-title-main">Interferon type I</span> Cytokine

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, IFNω (IFNW1), IFNɛ (IFNE), IFNк (IFNK) and IFNβ (IFNB1), plus 11 IFN pseudogenes.

<span class="mw-page-title-main">Interferon-alpha/beta receptor</span> Heterodimeric receptor

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.

<span class="mw-page-title-main">STAT1</span> Transcription factor and coding gene in humans

Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the STAT1 gene. It is a member of the STAT protein family.

<span class="mw-page-title-main">Toll-like receptor 7</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds. It is a member of the toll-like receptor (TLR) family and detects single stranded RNA.

<span class="mw-page-title-main">STAT4</span> Protein-coding gene in the species Homo sapiens

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient. STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12. There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma production downstream.

<span class="mw-page-title-main">STAT2</span> Protein-coding gene in Homo sapiens

Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene. It is a member of the STAT protein family. This protein is critical to the biological response of type I interferons (IFNs). STAT2 sequence identity between mouse and human is only 68%.

<span class="mw-page-title-main">Toll-like receptor 9</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289. It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells. TLR9 is expressed on endosomes internalized from the plasma membrane, binds DNA, and triggers signaling cascades that lead to a pro-inflammatory cytokine response. Cancer, infection, and tissue damage can all modulate TLR9 expression and activation. TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation.

<span class="mw-page-title-main">IFNA2</span> Mammalian protein found in Homo sapiens

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

<span class="mw-page-title-main">IRF5</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 5 is a protein that in humans is encoded by the IRF5 gene. The IRF family is a group of transcription factors that are involved in signaling for virus responses in mammals along with regulation of certain cellular functions.

<span class="mw-page-title-main">IRF8</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a protein that in humans is encoded by the IRF8 gene. IRF8 is a transcription factor that plays critical roles in the regulation of lineage commitment and in myeloid cell maturation including the decision for a common myeloid progenitor (CMP) to differentiate into a monocyte precursor cell.

<span class="mw-page-title-main">Lupus</span> Human autoimmune disease

Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face. Often there are periods of illness, called flares, and periods of remission during which there are few symptoms.

Anti-histone antibodies are autoantibodies that are a subset of the anti-nuclear antibody family, which specifically target histone protein subunits or histone complexes. They were first reported by Henry Kunkel, H.R. Holman, and H.R.G. Dreicher in their studies of cellular causes of lupus erythematosus in 1959–60. Today, anti-histone antibodies are still used as a marker for systemic lupus erythematosus, but are also implicated in other autoimmune diseases like Sjögren syndrome, dermatomyositis, or rheumatoid arthritis. Anti-histone antibodies can be used as a marker for drug-induced lupus.

<span class="mw-page-title-main">Anti-SSA/Ro autoantibodies</span> Type of anti-nuclear autoantibodies

Anti-SSA autoantibodies are a type of anti-nuclear autoantibodies that are associated with many autoimmune diseases, such as systemic lupus erythematosus (SLE), SS/SLE overlap syndrome, subacute cutaneous lupus erythematosus (SCLE), neonatal lupus and primary biliary cirrhosis. They are often present in Sjögren's syndrome (SS). Additionally, Anti-Ro/SSA can be found in other autoimmune diseases such as systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), rheumatoid arthritis (RA), and mixed connective tissue disease (MCTD), and are also associated with heart arrhythmia.

Anifrolumab, sold under the brand name Saphnelo, is a monoclonal antibody used for the treatment of systemic lupus erythematosus (SLE). It binds to the type I interferon receptor, blocking the activity of type I interferons such as interferon-α and interferon-β.

The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.

References

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