Disease relevance of IFNA1

• In this study, we examined the production of IFN-alpha and other cytokines by macrophage colony-stimulating factor (M-CSF)-treated cultured monocytes during HIV infection [1].
• Uninfected monocytes also produced high levels of IFN-alpha after treatment with poly(I).poly(C), Newcastle disease virus, or herpes simplex virus [1].
• In dose response studies, pretreatment with approximately 100 U/ml of IFN-alpha, approximately 10 U/ml of IFN-beta, or approximately 100 U/ml of IFN-gamma was sufficient to prevent virion release maximally and to prevent cytopathology completely [2].
• On 7 human melanoma cell lines (from 6 different patients), IFN-gamma had significantly greater direct anticellular effect than IFN-alpha or IFN-beta [3].
• The results not only confirmed the selective activity of IFN-gamma on the modulation of HLA-DR expression, as opposed to that of IFN-alpha, but also demonstrated a marked heterogeneity in the response of glioma cell lines and their clones to the two types of IFN tested [4].

Psychiatry related information on IFNA1

• Since conditions associated with an increased oxidative stress (advanced age, steatosis, fibrosis, iron overload, and alcohol consumption) reduce the likelihood of response, we hypothesized that oxidative stress may affect the antiviral actions of IFN-alpha [5].
• Alcohol abuse reduces response rates to IFN therapy in patients with chronic hepatitis C [6].
• This finding suggests that in the double TG mouse model mDCs once infected facilitate systemic MV spreading and infection, which depend on mDC MV permissiveness determined by the level of type I IFN generated via IFNAR1 [7].
• Our findings provided the first evidence showing that APOBEC3G is induced by IFN stimulation in human hepatocytes and thus could be involved in host defense mechanisms directed against hepatitis viruses [8].
• Forty-nine patients with CHC receiving IFN alpha at total dose of 480 MIU served as single therapy group [9].

High impact information on IFNA1

• Consequently, the role of IFN-alpha/beta in the pathogenesis of autoimmunity remains at the forefront of scientific inquiry and has begun to illuminate the mechanisms by which these molecules promote or inhibit systemic and organ-specific autoimmune diseases [10].
• Certain CpG motifs (CpG-A) are especially potent at activating NK cells and inducing IFN-alpha production by PDCs, while other motifs (CpG-B) are especially potent B cell activators [11].
• After binding to specific receptors on the surface of infected cells, IFN-alpha/beta has the potential to trigger the activation of multiple noncytolytic intracellular antiviral pathways that can target many steps in the viral life cycle, thereby limiting the amplification and spread of the virus and attenuating the infection [12].
• In addition to IFN-alpha/beta, a wide range of other innate cytokines can mediate biological functions regulating the NK cell responses of cytotoxicity, proliferation, and gamma interferon (IFN-gamma) production [13].
• Type I interferon (IFN-alpha and IFN-beta) is secreted by virus-infected cells [14].

Chemical compound and disease context of IFNA1

• The absence of detectable IFN-alpha activity and mRNA in poly(I).poly(C)-treated HIV-infected monocytes was coincident with high levels of 2',5' oligoadenylate synthetase and complete ablation of HIV gene expression [1].
• To determine the role of the Janus tyrosine kinase (JAK)-STAT pathway in NF-kappaB activation by IFN, we examined NF-kappaB activation in JAK1-deficient mutant human fibrosarcoma cells [15].
• We have expressed in Escherichia coli and COS 7 cells a soluble recombinant protein (sIFN-alpha R) comprising the extracellular domain of the hIFN-alpha R fused at the carboxyl terminus to a sequence of five histidine residues [16].
• CD8+ and CD8- subsets of peripheral blood natural killer (NK) cells were examined for susceptibility to infection with human immunodeficiency virus type 1 (HIV-1) and for the ability to produce various types of interferon (IFN) and tumor necrosis factor (TNF) [17].
• HIV production was significantly increased by antibodies to IFN-alpha in both untreated and vitamin D3-treated cultures [18].

Biological context of IFNA1

• Binding of interferons IFN-alpha and IFN-gamma to their cell surface receptors promptly induces tyrosine phosphorylation of latent cytoplasmic transcriptional activators (or Stat proteins, for signal transducers and activators of transcription) [19].
• Overall, our results reveal a wealth of new information regarding IFN/STAT-binding targets and also fundamental insights into mechanisms of regulation of gene expression in different cell states [20].
• Interferon (IFN) gamma, a cardinal proinflammatory cytokine, induces expression of the gene products of the class II locus of the major histocompatibility complex (MHC), whereas IFN-alpha or -beta suppresses MHC class II expression [21].
• Staphylococcal enterotoxin A (SEA) stimulated cord cell IFN gamma production at low cell densities; nevertheless, adult cells produced more IFN in response to SEA 1,341 +/- 350 U/ml) than cord cells (350 +/- 33 U/ml) [22].
• Upregulation of L-selectin surface density in IFN-alpha-treated Daudi B cells correlated directly with an increase in L-selectin mRNA steady state levels and enhanced L-selectin-dependent binding to a carbohydrate-based ligand, phosphomonoester core polysaccharide [23].

Anatomical context of IFNA1

• Analysis of the profile of IFNA genes expressed in virus-stimulated PDC, monocytes and MDDC demonstrated that each population expressed IFNA1 as the major subtype but that the range of the subtypes expressed in PDC was broader, with some donor and stimulus-dependent variability [24].
• Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the two individuals [25].
• We report here striking qualitative and quantitative differences in the intracellular response of human fibroblasts to IFN-gamma compared with IFN-alpha and IFN-beta [26].
• Furthermore, restoration of ISG15 conjugation in protein ISGylation-defective K562 cells increases IFN-stimulated promoter activity [27].
• Interferon alpha (IFN-alpha) induces significant antiretroviral activities that affect the ability of human immunodeficiency virus (HIV) to infect and replicate in its principal target cells, CD4+ T cells and macrophages [1].

Associations of IFNA1 with chemical compounds

• ISG15 is one of the most strongly induced genes upon viral infection, type I interferon (IFN) stimulation, and lipopolysaccharide (LPS) stimulation [27].
• The antiviral activity induced by poly(I).poly(C) may be a direct effect of this synthetic double-stranded RNA or secondary to the low levels of IFN-beta and IFN-omega produced by infected cells [1].
• Both IFN-gamma and type I IFNs (IFN-alpha or IFN-beta) induced 2'-5' oligoadenylate synthetase mRNA and enzyme activity in SMC cultures, but with concentration dependence and time course that may not account for all of IFN-gamma's cytostatic effect on SMC [28].
• Regardless of this, the antiviral activities of both IFN-alpha and IFN-gamma were attenuated by SB203580 [29].
• When analyzed by NaDodSO4/polyacrylamide gel electrophoresis the bulk of IFN activity not destroyed by NaDodSO4 treatment was recovered from two peaks with apparent molecular weights of 20,000 and 25,000 [30].

Physical interactions of IFNA1

• Importantly, the comparison of STAT1-binding sites upon interferon (IFN)-gamma and IFN-alpha treatments revealed dramatic changes in binding locations between the two treatments [20].
• The IFNAR chain interacts with both IFN-alpha 2 and IFN-beta, as demonstrated by cross-linking [31].
• Antibodies against a peptide with the CR2 binding sequence on C3d react with a peptide carrying the IFN alpha CR2 binding motif (residues 92-99) and with recombinant IFN alpha [32].
• A maximal increase in TNF binding was seen after about 6 to 12 hr of incubation with IFN [33].
• We demonstrate that IFN-alpha will induce the binding of IRF-1 and Stat3 to the respective motifs [34].

Enzymatic interactions of IFNA1

• Using these, we have identified tyk2 as a 134-kDa protein which is rapidly and transiently phosphorylated on tyrosine in response to IFN-alpha/beta and possesses an inducible kinase activity when tested in vitro [35].
• Type I interferon (IFN) stimulates transcription through a heteromeric transcription factor that contains tyrosine-phosphorylated STAT2 [36].
• Analysis of phosphopeptide binding analysis suggests that Stat4 does not interact directly with tyrosine-phosphorylated amino acid residues within the cytoplasmic domains of either of the subunits of the IFN-alpha receptor complex [37].
• Interferon (IFN) induces gene expression by phosphorylating latent transcription factors of the STAT family [38].
• Three sequence-tagged site markers in the region bordered by HIFN alpha and D9S171 were used to further map the deleted region by multiplex polymerase chain reaction with the HIFN gamma maker (on chromosome 12) as a control for amplification [39].

Regulatory relationships of IFNA1

• Interferon (IFN) activates the signal transducer and activator of transcription (STAT) pathway to regulate immune responses [40].
• Both are IFN dependent and abrogated by a monoclonal antibody which blocks IFNAR action [31].
• Transient overexpression of IRF9 reproduced the drug-resistance phenotype and induced expression of IFN-responsive genes [41].
• When macrophages were pretreated with low doses of IFN-gamma and then stimulated with IFN-alpha, clearly enhanced formation of specific transcription factor complexes was detected [42].
• In turn, the autocrine production of IFN-beta induces the IFN-stimulated genes that contain binding sites for activated STATs in their promoters [43].

Other interactions of IFNA1

• Neither IFN-alpha/beta nor IFN-gamma activated STAT1-containing transcription factors [25].
• Different pathways mediate virus inducibility of the human IFN-alpha 1 and IFN-beta genes [44].
• Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease [25].
• Differential tyrosine phosphorylation of the IFNAR chain of the type I interferon receptor and of an associated surface protein in response to IFN-alpha and IFN-beta [31].
• CR2 or CR2-like molecules may therefore be the major IFN alpha receptors on B lymphocytes [32].

Analytical, diagnostic and therapeutic context of IFNA1

• These data together with the results of two-step chromatin immunoprecipitation strongly suggest that the IRF-3 and IRF-7 bind to IFNA1 promoter as a dimer [45].
• Sequence determination of cloned cDNAs and genes of the three classes of interferon (IFN-alpha, -beta and -gamma) has revealed more than a dozen members of the human IFN-alpha gene family and a single gene for IFN-beta [46].
• In marked contrast to the preceding observations, HIV-infected monocytes produced little or no IFN-alpha before or after treatment with any of these agents [1].
• As shown by mobility shift assays, this complex was not formed in the nuclear extracts of IFN-treated adenovirus-infected cells or IFN-treated E1A-producing cells [47].
• Together, these data indicate an exquisite sensitivity of monocyte-derived DCs to activation-induced cell death if generated in the presence of IFN-alpha, indicating the existence of an important mechanism of immunosuppression caused by IFN-alpha-inducing agents, such as viral or bacterial stimuli [48].

References