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Interferon alpha-1

This article was updated by an external expert under a dual publication model. The corresponding peer-reviewed article was published in the journal Gene. Click to view.
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IFNA1
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesIFNA1, IFL, IFN, IFN-ALPHA, IFN-alphaD, IFNA13, IFNA@, Interferon, alpha 1, interferon alpha 1, leIF D
External IDsOMIM: 147660; HomoloGene: 136811; GeneCards: IFNA1; OMA:IFNA1 - orthologs
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 Mbn/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]

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

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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

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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

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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

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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

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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

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000197919 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  4. ^ a b "Entrez Gene: IFNA1 interferon, alpha 1".
  5. ^ Lengyel P (1982). "Biochemistry of interferons and their actions". Annual Review of Biochemistry. 51: 251–82. doi:10.1146/annurev.bi.51.070182.001343. PMID 6180680.
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  7. ^ Isaacs A, Lindenmann J (Sep 1957). "Virus interference. I. The interferon". Proceedings of the Royal Society of London. Series B, Biological Sciences. 147 (927): 258–67. Bibcode:1957RSPSB.147..258I. doi:10.1098/rspb.1957.0048. PMID 13465720. S2CID 202574492.
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  21. ^ Weckerle CE, Franek BS, Kelly JA, Kumabe M, Mikolaitis RA, Green SL, Utset TO, Jolly M, James JA, Harley JB, Niewold TB (Apr 2011). "Network analysis of associations between serum interferon-α activity, autoantibodies, and clinical features in systemic lupus erythematosus". Arthritis and Rheumatism. 63 (4): 1044–53. doi:10.1002/art.30187. PMC 3068224. PMID 21162028.
  22. ^ Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW (Mar 2003). "Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus". Proceedings of the National Academy of Sciences of the United States of America. 100 (5): 2610–5. Bibcode:2003PNAS..100.2610B. doi:10.1073/pnas.0337679100. PMC 151388. PMID 12604793.
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  24. ^ a b Niewold TB (Jun 2008). "Interferon alpha-induced lupus: proof of principle". Journal of Clinical Rheumatology. 14 (3): 131–2. doi:10.1097/RHU.0b013e318177627d. PMC 2743115. PMID 18525429.
  25. ^ Niewold TB, Hua J, Lehman TJ, Harley JB, Crow MK (Sep 2007). "High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus". Genes and Immunity. 8 (6): 492–502. doi:10.1038/sj.gene.6364408. PMC 2702174. PMID 17581626.
  26. ^ Cherian TS, Kariuki SN, Franek BS, Buyon JP, Clancy RM, Niewold TB (Oct 2012). "Brief Report: IRF5 systemic lupus erythematosus risk haplotype is associated with asymptomatic serologic autoimmunity and progression to clinical autoimmunity in mothers of children with neonatal lupus". Arthritis and Rheumatism. 64 (10): 3383–7. doi:10.1002/art.34571. PMC 3449035. PMID 22674082.
  27. ^ Niewold TB, Kelly JA, Kariuki SN, Franek BS, Kumar AA, Kaufman KM, Thomas K, Walker D, Kamp S, Frost JM, Wong AK, Merrill JT, Alarcón-Riquelme ME, Tikly M, Ramsey-Goldman R, Reveille JD, Petri MA, Edberg JC, Kimberly RP, Alarcón GS, Kamen DL, Gilkeson GS, Vyse TJ, James JA, Gaffney PM, Moser KL, Crow MK, Harley JB (Mar 2012). "IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus". Annals of the Rheumatic Diseases. 71 (3): 463–8. doi:10.1136/annrheumdis-2011-200463. PMC 3307526. PMID 22088620.
  28. ^ Tezak Z, Hoffman EP, Lutz JL, Fedczyna TO, Stephan D, Bremer EG, Krasnoselska-Riz I, Kumar A, Pachman LM (Apr 2002). "Gene expression profiling in DQA1*0501+ children with untreated dermatomyositis: a novel model of pathogenesis". Journal of Immunology. 168 (8): 4154–63. doi:10.4049/jimmunol.168.8.4154. PMID 11937576.
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  30. ^ Zhou X, Dimachkie MM, Xiong M, Tan FK, Arnett FC (Jul 2004). "cDNA microarrays reveal distinct gene expression clusters in idiopathic inflammatory myopathies". Medical Science Monitor. 10 (7): BR191–7. PMID 15232492.
  31. ^ Baechler EC, Bauer JW, Slattery CA, Ortmann WA, Espe KJ, Novitzke J, Ytterberg SR, Gregersen PK, Behrens TW, Reed AM (2007). "An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity". Molecular Medicine. 13 (1–2): 59–68. doi:10.2119/2006-00085.Baechler. PMC 1869622. PMID 17515957.
  32. ^ Niewold TB, Kariuki SN, Morgan GA, Shrestha S, Pachman LM (Oct 2010). "Gene-gene-sex interaction in cytokine gene polymorphisms revealed by serum interferon alpha phenotype in juvenile dermatomyositis". The Journal of Pediatrics. 157 (4): 653–7. doi:10.1016/j.jpeds.2010.04.034. PMC 2936662. PMID 20605164.
  33. ^ Niewold TB, Wu SC, Smith M, Morgan GA, Pachman LM (May 2011). "Familial aggregation of autoimmune disease in juvenile dermatomyositis". Pediatrics. 127 (5): e1239–46. doi:10.1542/peds.2010-3022. PMC 3081190. PMID 21502224.
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  35. ^ Reder AT, Feng X (2013). "Aberrant Type I Interferon Regulation in Autoimmunity: Opposite Directions in MS and SLE, Shaped by Evolution and Body Ecology". Frontiers in Immunology. 4: 281. doi:10.3389/fimmu.2013.00281. PMC 3775461. PMID 24062747.
  36. ^ Comabella M, Lünemann JD, Río J, Sánchez A, López C, Julià E, Fernández M, Nonell L, Camiña-Tato M, Deisenhammer F, Caballero E, Tortola MT, Prinz M, Montalban X, Martin R (Dec 2009). "A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis". Brain. 132 (Pt 12): 3353–65. doi:10.1093/brain/awp228. PMID 19741051.
  37. ^ Feng X, Reder NP, Yanamandala M, Hill A, Franek BS, Niewold TB, Reder AT, Javed A (Feb 2012). "Type I interferon signature is high in lupus and neuromyelitis optica but low in multiple sclerosis". Journal of the Neurological Sciences. 313 (1–2): 48–53. doi:10.1016/j.jns.2011.09.032. PMC 3910514. PMID 22036215.
  38. ^ Wallace DJ, Petri M, Olsen N, Kirou K, Dennis G, Yao Y, et al. (2007). "MEDI-545, an anti-interferon alpha monoclonal antibody, shows evidence of clinical activity in systemic lupus erythematosus". Arthritis Rheum. 56: S526 – S527.
  39. ^ Yao Y, Richman L, Higgs BW, Morehouse CA, de los Reyes M, Brohawn P, Zhang J, White B, Coyle AJ, Kiener PA, Jallal B (Jun 2009). "Neutralization of interferon-alpha/beta-inducible genes and downstream effect in a phase I trial of an anti-interferon-alpha monoclonal antibody in systemic lupus erythematosus". Arthritis and Rheumatism. 60 (6): 1785–96. doi:10.1002/art.24557. PMID 19479852.
  40. ^ Mavragani CP, La DT, Stohl W, Crow MK (Feb 2010). "Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon-beta/alpha ratios in rheumatoid arthritis patients: a post hoc analysis of a predominantly Hispanic cohort". Arthritis and Rheumatism. 62 (2): 392–401. doi:10.1002/art.27226. PMC 2821991. PMID 20112385.
  41. ^ Thurlings RM, Boumans M, Tekstra J, van Roon JA, Vos K, van Westing DM, van Baarsen LG, Bos C, Kirou KA, Gerlag DM, Crow MK, Bijlsma JW, Verweij CL, Tak PP (Dec 2010). "Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients". Arthritis and Rheumatism. 62 (12): 3607–14. doi:10.1002/art.27702. PMID 20722020.
[edit]
  • Overview of all the structural information available in the PDB for UniProt: P01562 (Interferon alpha-1/13) at the PDBe-KB.
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