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Results for “Type I interferon”

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PubMed1990

Synergism of type I and type II interferons in stimulating the activity of the same DNA enhancer.

Type I and type II interferons (IFNs) can act synergistically to activate the transcription of the 2-5A synthetase gene. We used in vivo functional assays of sequences from the gene promoter region to determine which DNA segment mediates the gene induction by IFN gamma and the synergistic effect. We found that the type I IFN-inducible enhancer (or IRS) of the 2-5A synthetase gene also confers inducibility by type II IFN to a reporter CAT gene, though the time course and dose response of the induction by the two IFNs are quite different. A clear synergism of the two IFN in stimulating the IRS is observed at low doses of the two IFNs.

Base Sequence↗

PubMed1999

Formation of a uniquely stable type I interferon receptor complex by interferon beta is dependent upon particular interactions between interferon beta and its receptor and independent of tyrosine phosphorylation.

Human type I interferons (IFN) require two receptor chains, IFNAR1 and IFNAR2c for high affinity (pM) binding and biological activity. Our previous studies have shown that the ligand dependent assembly of the type I IFN receptor chains is not identical for all type I IFNs. IFNbeta appears unique in its ability to assemble a stable complex of receptor chains, as demonstrated by the observation that IFNAR2c co-immunoprecipitates with IFNAR1 when cells are stimulated with IFNbeta but not with IFNalpha. The characteristics of such a receptor complex are not well defined nor is it understood if differential signaling events can be mediated by variations in receptor assembly. To further characterize the factors required for formation of such a stable receptor complex we demonstrate using IFN stimulated Daudi cells that (1) IFNAR2c co-immunoprecipitates with IFNAR1 even when tyrosine phosphorylation of receptor chains is blocked with staurosporine, and (2) IFNbeta1b but not IFNalpha2, is present in the immunoprecipitated receptor complex. These results demonstrate that the unique IFNbeta induced assembly of type I IFN receptor chains is independent of receptor tyrosine phosphorylation and the recruitment of additional proteins to the receptor by such events. Furthermore, the presence of IFNbeta1b in the immunoprecipitated IFN receptor complex suggests that IFNbeta interacts and binds differently to the receptor than IFNalpha2. These results suggest that the specific assembly of type I IFN receptor chains is ligand dependent and may represent an early event which leads to the differential biological responses observed among type I IFNs.

Humans↗

PubMed2004

A C-terminal basic amino acid motif of Zaire ebolavirus VP35 is essential for type I interferon antagonism and displays high identity with the RNA-binding domain of another interferon antagonist, the NS1 protein of influenza A virus.

The ebolavirus VP35 protein antagonizes the cellular type I interferon response by blocking phosphorylation of IRF-3, a transcription factor that turns on the expression of a large number of antiviral genes. To identify the domain of VP35 responsible for interferon antagonism, we generated mutations within the VP35 gene and found that a C-terminal basic amino acid motif is required for inhibition of ISG56 reporter gene expression as well as IFN-beta production. Remarkably, this basic amino acid motif displayed high sequence identity with part of the N-terminal RNA-binding domain of another interferon-antagonist, the NS1 protein of influenza A virus.

Amino Acid Motifs↗

PubMed1992

Type I interferons (IFN-alpha and -beta) suppress cytotoxin (tumor necrosis factor-alpha and lymphotoxin) production by mitogen-stimulated human peripheral blood mononuclear cell.

We studied the effect of the different types of interferons on the production of cytotoxin by human peripheral blood mononuclear cells (PBMCs) stimulated with the mitogen phytohemagglutinin (PHA). Maximum secreted levels of cytotoxin were observed at day 3 in culture and consisted of both tumor necrosis factor alpha (TNF-alpha) and lymphotoxin as determined by specific antibodies. Type I interferons (IFN-alpha and IFN-beta) consistently suppressed cytotoxin production. Both TNF-alpha and lymphotoxin were significantly suppressed. Mean suppression by IFN-alpha and IFN-beta (1000 U/ml) was 56 and 66%, respectively, in PBMCs from 18 different donors. The suppressive effects of IFN-alpha and IFN-beta on cytotoxin production were dose responsive over a range of 10 to 1000 U/ml. Type II interferon (IFN-gamma) did not have consistent significant effects. Pretreatment with IFN-alpha or IFN-beta for 24 or 48 h prior to PHA stimulation also resulted in significant suppression. Supplementation with interleukin-2 (10 U/ml) or IFN-gamma (1000 U/ml) did not overcome cytotoxin suppression by IFN-alpha or IFN-beta. Cytotoxin suppression by IFN-alpha and IFN-beta together appeared to be noninteractive. Suppression appeared not to be due to blockade of the cytotoxin release, since both cell-associated cytotoxin and secreted cytotoxin were suppressed to the same level. These results demonstrated that cytotoxin and lymphotoxin production by PHA-stimulated PBMCs could be down-regulated by type I interferons and that there is a substantial difference between the action of type I interferons and type II interferons (IFN-gamma) in modulating the biosynthesis of cytotoxins.

Cells, Cultured↗

PubMed2005

Respiratory syncytial virus nonstructural protein 2 specifically inhibits type I interferon signal transduction.

Human respiratory syncytial virus (RSV) inhibits type I interferon-induced gene expression by decreasing expression of signal transducer and activator of transcription (Stat)2. To identify the RSV protein that mediates effects on Stat2, airway epithelial cells were infected with vaccinia virus vectors that express single RSV proteins. Expression of RSV nonstructural (NS)2 protein alone was sufficient to decrease Stat2 levels. Furthermore, decreasing RSV NS2 levels using RNA interference in respiratory epithelial cells inhibited the RSV-mediated decrease in Stat2 expression. Airway epithelial cells were also infected with equivalent inoculums of RSV without or with single gene deletions of NS1 or NS2. RSV infection without NS2 expression did not result in decreased Stat2 levels or loss of type I interferon-dependent signaling, indicating that NS2 expression is necessary for RSV effects on Stat2. Taken together, our results indicate that NS2 regulates Stat2 levels during RSV infection, thereby modulating viral effects on interferon-dependent gene expression.

Cells, Cultured↗

PubMed1995

The evolution of the type I interferon gene family in mammals.

A phylogenetic analysis of mammalian type I interferon (IFN) genes showed: (1) that the three main subfamilies of these genes in mammals (IFN-beta, IFN-alpha, and IFN-omega) diverged after the divergence of birds and mammals but before radiation of the eutherian orders and (2) that IFN-beta diverged first. Although apparent cases of interlocus recombination among mouse IFN-alpha genes were identified, the hypothesis that coding regions of IFN-alpha genes have been homogenized within species by interlocus recombination was not supported. Flanking regions as well as coding regions of IFN-alpha were more similar within human and mouse than between these species; and reconstruction of the pattern of nucleotide substitution in IFN-alpha coding regions of four mammalian species by the maximum parsimony method suggested that parallel substitutions have occurred far more frequently between species than within species. Therefore, it seems likely that IFN-alpha genes have duplicated independently within different eutherian orders. In general, type I IFN genes are subject to purifying selection, which in the case of IFN-alpha and IFN-beta is strongest in the putative receptor-binding domains. However, analysis of the pattern of nucleotide substitution among IFN-omega genes suggested that positive Darwinian selection may have acted in some cases to diversify members of this subfamily at the amino acid level.

Amino Acid Sequence↗

PubMed2005

Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus.

Recent studies have suggested that type I interferons (IFN) play a role in the pathogenesis of lupus erythematosus (LE), an autoimmune disease of unknown aetiology. Natural interferon-producing plasmacytoid cells have been demonstrated in cutaneous LE (CLE) lesions, along with elevated levels of IFN-alpha mRNA. The hypothesis in the current study was that local production of type I IFNs in CLE induces Th1-biased inflammation via induction of IFN-inducible chemokines such as IP10/CXCL10 leading to the recruitment of chemokine receptor CXCR3 expressing T-cells into skin lesions. Skin biopsies from 21 patients suffering from different types of active cutaneous LE were analysed for the expression of MxA, a protein specifically induced by type I interferons, the IFN-inducible protein IP10/CXCL10, and the chemokine receptor CXCR3, characteristic for Th1 cells, by immunohistochemistry. Additionally, peripheral CD4+ and CD8+ T-cells were investigated for the expression of MxA and CXCR3 by flow cytometry. Cutaneous LE lesions were characterized by strong expression of MxA indicating the induction of localized type I IFN signalling in the skin. Large numbers of infiltrating CXCR3 positive lymphocytes were detected in CLE skin lesions, and correlated closely with lesional MxA expression (epidermis: Spearman's rho = 0.56, p < 0.001; dermis: rho = 0.82, p < 0.001). Intracellular MxA levels of circulating CD4+ and CD8+ T-cells were significantly enhanced in patients with active CLE lesions. The percentage of peripheral T-cells expressing CXCR3 was significantly decreased in specific CLE subtypes. Expression of IP10/CXCL10 in the epidermis links type I IFN signalling and recruitment of CXCR3+ T cells. These results suggest an important role for type I interferon signalling in the pathogenesis of cutaneous lupus erythematosus. It is proposed that type I IFNs induce a Th1-biased inflammatory immune response, with recruitment of CXCR3-expressing T-lymphocytes into the skin.

CD8-Positive T-Lymphocytes↗

PubMed2002

Enhanced tumor development in mice lacking a functional type I interferon receptor.

The aim of this study was to investigate the contribution of endogenous - that is, without the addition of any interferon (IFN) inducer - type I IFN production in the defense against tumor development. To this purpose, the IFN-alpha receptor (IFNAR) knockout (KO)-induced mutation, resulting in the complete absence of IFN-alpha/beta activity, was introduced into a C3H genetic background by 10 backcross generations, followed by brother-sister matings for at least four generations. The resulting mice were inoculated either with syngeneic C3H melanoma K1735 cells, with allogeneic 3LL carcinoma cells, or with allogeneic B16F10 melanoma cells. With all three tumor cell lines, tumor development and ensuing mortality were enhanced in the IFNAR KO animals. This indicates that endogenous IFN-alpha/beta production is a mediator of natural immunity to tumor development.

Animals↗

PubMed2001

Low-dose orally administered type I interferon reduces splenic B cell numbers in mice.

The beneficial effects of low-dose orally administered type I interferon (LDOA IFN) have been demonstrated in various animal models of disease and in some human clinical trials. The mechanisms by which LDOA IFN therapy has its effects, however, remain to be established. In the present study, groups of mice were administered 10 IU murine IFN-alpha/beta (MuIFN-alpha/beta) orally for 7 days. Spleens were then collected and analyzed. No differences were detected between the spleen weights of treated mice compared with controls, although reductions in total splenic white blood cell (WBC) number ranging from 15.5% to 35% were observed. Further analysis showed this reduction to be largely restricted to the B cell population, with only minor reductions in CD4(+) or CD8(+) populations being detected. Dose-response studies showed the WBC loss from the spleen to be optimal at 1 IU MuIFN-alpha/beta, whereas both higher and lower doses showed less significant effects. Time course studies show these effects had developed after 2 days of treatment. It is hypothesized that this observed WBC movement from the spleen is part of the mechanism of action of LDOA IFN.

Administration, Oral↗

PubMed2002

Type I interferons as immunoregulatory molecules; implications for therapy in experimental autoimmune uveoretinitis.

Clinical trials have shown that the type I interferon (IFN)-alpha/beta have some beneficial effects on organ-specific autoimmune diseases, such as Behcet's diseases and multiple sclerosis, although the precise mechanisms remain largely unresolved. T helper cells 1 (Th1)-mediated autoimmune responses are involved in the initiation and/or progression of human uveitis, such as Behcet's disease. The animal model of experimental autoimmune uveoretinitis (EAU), characterized by a monophasic clinical course, has contributed to the understanding of the pathogenesis of human uveitis. Th1 producing IFN-gamma induce EAU development, while Th2 producing IL-4/IL-10 prevent the disease. However, depending on the cytokine milieu, the pro-inflammatory cytokine IFN-gamma may attenuate the autoimmune responses and anti-inflammatory cytokine IL-4 exacerbates it. Chemokines also play a crucial role in EAU development, which might be resolved by Th2-mediated immune responses. The administration of IFN-alpha/beta prevents EAU development, accompanied by a diminished production of IFN-gamma/IL-10. Interestingly, however, IFN-alpha/beta also have some beneficial effects on patients with Th2-like phenotype in addition to Th1-like phenotypes. Thus, the immuno-modulatory action of IFN-alpha/beta may be dependent on the context of cytokine combination and/or their concentrations.

Animals↗

PubMed1994

Differential expression patterns of type I interferon subtypes in mouse embryo fibroblasts: influence of genotype and viral inducer.

Primary mouse embryo fibroblasts from 4 strains of mice (BALB/c, C57Bl/6, B6.C-H-28c and CBA) were infected with either Newcastle disease virus or murine cytomegalovirus. The time course of the total type I interferon response was assessed and the presence of individual subtypes determined. The total type I interferon produced was titrated using the cytopathic effect reduction assay and the relative levels of type I interferon subtypes expressed (alpha 1, alpha 4, alpha 5, alpha 6 and beta) were evaluated using a reverse transcription-polymerase chain reaction-based technique. In general, the patterns of type I interferon subtypes expressed appeared to be determined by the strain of mouse cells used rather than the inducing virus. However, the overall titre of type I interferons produced in response to a given virus was quite uniform across the strains of mice from which the mouse embryo fibroblasts were derived regardless of the subtype expression pattern. The latter observation fits the proposition that "cross-talk" or feedback between the type I interferon genes and their products is is occurring and that the inducer determines the level of response.

Animals↗

PubMed2002

Type I interferons inhibit interleukin-10 production in activated human monocytes and stimulate IL-10 in T cells: implications for Th1-mediated diseases.

Type I interferons (IFNs) directly induce development of Th1 cells. However, IFN-alpha and IFN-beta should generate Th2 cells because these IFNs induce interleukin-10 (IL-10) and block secretion of IFN-gamma. We hypothesized that paradoxical effects of IFNs on Th1-mediated immunity could be from monocyte-specific and T cell-specific IL-10 regulation. We demonstrate that IFN-alpha and IFN-beta inhibit IL-10 mRNA and protein production by activated monocytes but stimulate IL-10 production by activated T cells from the same healthy donors. Without IFN-beta, Staphylococcus aureus, Cowan strain I (SAC)-activated monocytes secreted 15-fold more IL-10 than phorbol myristate acetate (PMA) anti-CD3-activated T cells. With IFN-beta, the two subsets had nearly equivalent secretion. Prostaglandin (PGE) and other cAMP agonists had subset-specific effects on IL-10 production opposite to IFN-beta. The differential IFN-beta effect on transcriptional regulation of IL-10 in monocytes and T cells was from lineage-specific modification of RNA stability. IFN-beta decreased the half-life of IL-10 mRNA in activated monocytes but prolonged the half-life in activated T cells. Subset-specific IL-10 regulation has important implications for Th1-mediated disease. When activated macrophages and microglia are in excess, as in rheumatoid joints or possibly in chronic multiple sclerosis brain lesions, IFNs may inhibit overall IL-10 production and worsen disease. When T cells outnumber monocytes, IFN-beta will induce IL-10 and ameliorate Th1-mediated disease.

Cells, Cultured↗

PubMed2005

Depletion of T cells by type I interferon: differences between young and aged mice.

Type I IFN (IFN-I or IFN-alphabeta) plays an important role in the innate immune response against viral infection. Here we report that a potent inducer of IFN-alphabeta, polyinosinic-polycytidylic acid [poly(I:C)], led to the depletion of T cells in young, but not aged mice, and that this depletion was limited to central memory, but not effector memory, T cells. Although early activation of T cells in vivo by poly(I:C), as demonstrated by CD69, was not impaired with aging, the expression of active caspase-3 was higher in young compared with aged mice. This depletion of T cells and induction of active caspase-3 in young mice and of CD69 in both young and aged mice by poly(I:C) were blocked by anti-IFN-alphabeta Ab. Although poly(I:C) stimulated lower circulating levels of IFN-alphabeta in aged mice, administration of IFN-alphabeta after poly(I:C) did not induce depletion of T cells in aged mice. These results indicate that IFN-alphabeta plays a critical role in the depletion of T cells of young mice, and further suggest that the lower level of functional IFN-alphabeta and decreased induction of active caspase-3 in T cells of aged mice after poly(I:C) may be responsible for the increased resistance of T cells of aged mice to depletion.

Aging↗

PubMed2006

Type I interferon production in HIV-infected patients.

Type I IFNs display multiple biological effects. They have a strong antiviral action, not only directly but also indirectly through activation of the immune system. They may also have actions that are deleterious for the host. The cells that produce type I IFN are mostly plasmacytoid dendritic cells (pDC), but this depends on the viral stimulus. The migration and distribution of pDC into lymphoid organs, driven by chemokine interactions with their ligands, determines interaction with different cell types. In HIV infection, IFN production in vitro is impaired during primary infection and later in association with opportunistic infections. Circulating pDC numbers are decreased in parallel. These parameters may be used to help assess the prognosis of the disease and to monitor treatment.

Animals↗

PubMed1994

Mice devoid of interferon regulatory factor 1 (IRF-1) show normal expression of type I interferon genes.

The transcription factor interferon regulatory factor 1 (IRF-1) binds tightly to the interferon (IFN)-beta promoter and has been implicated in the induction of type I IFNs. We generated mice devoid of functional IRF-1 by targeted gene disruption. As reported by others, IRF-1-deficient mice showed a discrete phenotype: the CD4/CD8 ratio was increased and IFN-gamma-induced levels of macrophage iNO synthase mRNA were strongly diminished. However, type I IFN induction in vivo by virus or double-stranded RNA was unimpaired, as evidenced by serum IFN titers and IFN mRNA levels in spleen, liver and lung. There was also no impairment in the response of type I IFN-inducible genes. Therefore, IRF-1 is not essential for these processes in vivo.

Animals↗

PubMed2003

The human type I interferon receptor: NMR structure reveals the molecular basis of ligand binding.

The potent antiviral and antiproliferative activities of human type I interferons (IFNs) are mediated by a single receptor comprising two subunits, IFNAR1 and IFNAR2. The structure of the IFNAR2 IFN binding ectodomain (IFNAR2-EC), the first helical cytokine receptor structure determined in solution, reveals the molecular basis for IFN binding. The atypical perpendicular orientation of its two fibronectin domains explains the lack of C domain involvement in ligand binding. A model of the IFNAR2-EC/IFNalpha2 complex based on double mutant cycle-derived constraints uncovers an extensive and predominantly aliphatic hydrophobic patch on the receptor that interacts with a matching hydrophobic surface of IFNalpha2. An adjacent motif of alternating charged side chains guides the two proteins into a tight complex. The binding interface may account for crossreactivity and ligand specificity of the receptor. This molecular description of IFN binding should be invaluable for study and design of IFN-based biomedical agents.

Humans↗

PubMed2006

Systemic lupus erythematosus: all roads lead to type I interferons.

In recent years, the study of systemic lupus erythematosus (SLE) patients has revealed a central role for type I interferon (IFN) in disease pathogenesis. IFN induces the unabated activation of peripheral dendritic cells, which select and activate autoreactive T cells rather than deleting them, thus failing to induce peripheral tolerance. IFN also directly affects T cells and B cells. Furthermore, immune complexes binding to FcgammaR and Toll-like receptors provide an amplification loop for IFN production and B-cell activation in SLE. Polymorphisms in genes that control IFN production or its downstream signaling pathway, such as IRF5, might be responsible for some of these alterations. This novel information is leading to the development of IFN antagonists as a potential therapeutic intervention in SLE, thus bringing hope to SLE patients.

Animals↗

PubMed1980

Immunoregulatory action of type I interferon in the mouse.

The effect of type I interferon production on immunity to the interferon-inducing virus was examined using the Newcastle disease virus [NDV]-mouse model and comparing If-1h and If-1l animals. The degree of cell-mediated immunity, as measured by delayed hypersensitivity [DH] to NDV, was influenced by the levels of interferon produced. Anti-interferon globulin given immediately after immunization decreased sensitization to NDV, whereas additional, exogenous, interferon, given to low interferon producers, stimulated sensitization to NDV. The alleles at the If-1 locus influenced the extent of DH to NDV, in that If-1h mice developed much stronger DH than did If-1l mice. However, results from recombinant inbred strains, F2 and backcross generations showed that for interferon production to stimulate DH to NDV, other genes, present in the C57BL/6 background but as yet not characterized, are required. Thus DH to NDV is determined on the one hand by the alleles at If-1, influencing interferon production, and on the other hand by a combination of several genes affecting the interaction of interferon with cells of the immune system.

Animals↗