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Results for “Type I interferon”

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PubMed1980

Nonspecific inhibition of encephalomyocarditis virus replication by a type II interferon released from unstimulated cells of Mycobacterium tuberculosis-sensitized mice.

Unstimulated peritoneal cells (PC) from mice sensitized with nonviable Mycobacterium tuberculosis in an oil-droplet emulsion inhibit encephalomyocarditis virus (EMCV) replication in mouse embryo fibroblast monolayers. Concentrations of mycobacteria ranging from 50 to 500 microgram elicit PC that inhibit EMCV replication greater than 99%. PC collected 2 to 6 weeks post-inoculation of mycobacteria are most effective (greater than 99% inhibition), although cells harvested from mice 7 through 10 weeks inhibit viral replication greater than 90%. Inhibition of replication is not detected unless PC are in contact with infected monolayers for a minimum of 8 to 10 hr; nonviable PC are not effective. Optimal inhibition occurs in cultures infected with a low multiplicity of EMCV that are incubated at 37 degrees C. Inhibition of replication is not due to pH changes or depletion of nutrients in cultures, adsorption and/or inactivation of EMCV by macrophages, or killing of monolayers by the PC. Inhibition of viral replication by the unstimulated PC appears to be due to an interferon that is similar but not identical to classical mouse Type II interferon.

Animals↗

PubMed2006

Blockade of TLR9 agonist-induced type I interferons promotes inflammatory cytokine IFN-gamma and IL-17 secretion by activated human PBMC.

Type I interferons (IFN) (IFN-alpha/beta) are recognized as both inhibitors and effectors of autoimmune disease. In multiple sclerosis, IFN-beta therapy appears beneficial, in part, due to its suppression of autoimmune inflammatory Th cell responses. In contrast, in systemic lupus erythematosus (SLE) triggering of plasmacytoid DC (pDC) Toll-like receptors (TLRs) by autoimmune complexes (autoICs) results in circulating type I IFN that appear to promote disease by driving autoantigen presentation and autoantibody production. To investigate how pDC-derived type I IFN might regulate Th cells in SLE, we examined a model in which sustained pDC stimulation by autoICs is mimicked by pretreating normal human PBMC with TLR9 agonist, CpG-A. Subsequently, PBMC Th cells are activated with superantigen, and APC are activated with CD40L. The role of CpG-A/TLR9-induced type I IFN in regulating PBMC is determined by blocking with virus-derived soluble type I IFN receptor, B18R. In summary, pretreatment with either rhIFN-alpha/beta or CpG-A inhibits PBMC secretion of superantigen-induced IFN-gamma and IL-17, and CD40L-induced IL-12p70 and IL-23. B18R prevents these effects. Data indicate that CpG-A-induced type I IFN inhibit IL-12p70-dependent PBMC IFN-gamma secretion by enhancing IL-10. Our results suggest that in SLE, circulating type I IFN may potentially act to inhibit inflammatory cytokine secretion.

Antigen Presentation↗

PubMed1994

Identification of functional type I and type II interferon receptors.

Although the interferons were the first cytokines purified and cloned, their receptors have remained an enigma as fully functional receptors have not been defined and characterized. We previously discovered that the IFN-gamma receptor (IFN-gamma R) was able to bind IFN-gamma, but required one or more accessory factors to exhibit functional activity. We have now identified a gene and sequence of one of these accessory factors. Both genomic and cDNA clones were used to reconstitute a functional receptor. The presence of the Hu-IFN-gamma R and the human accessory factor-1 (designated AF-1) are both necessary and sufficient to induce MHC class I antigens in response to Hu-IFN-gamma in hamster cells. AF-1 is a transmembrane protein with no significant amino acid homology to other sequences in nucleic acid data bases, but has overall structural homology to the class 2 cytokine receptor family. Whereas total human DNA was used to first isolate a Type I interferon receptor, the only genomic or cDNA clone reported exhibited activity essentially only in response to Hu-IFN-alpha B2 (Hu-IFN-alpha 8). Yet hamster or mouse cells containing human Chromosome 21 seemed to have the full complement of Hu-IFN-alpha activities and responded to all Hu-IFN-alpha species as well as Hu-IFN-beta. To investigate this dilemma, we extended our earlier studies with total human DNA to employ defined YAC clones. We have now isolated a genomic segment of human Chromosome 21 that exhibits the properties expected of the Type I interferon receptor: response to multiple species of Hu-IFN-alpha; and excellent binding of Hu-IFN-alpha A and Hu-IFN-alpha B2 species. Reconstitution of functional Type I and Type II interferon receptors now provides the first steps to link the receptors to the signal transduction mechanisms; and will help to integrate our understanding of the ligand receptor interactions to the molecular signals that activate specific transcription factors that in turn induce specific genes carrying the interferon regulatory elements.

Animals↗

PubMed2004

Type I interferon sensitizes lymphocytes to apoptosis and reduces resistance to Listeria infection.

Infection with Listeria monocytogenes causes lymphocyte apoptosis that is mediated by the actions of the pore-forming virulence factor listeriolysin O (LLO). Previous work showed that activated lymphocytes were highly sensitive to LLO-induced apoptosis, whereas resting lymphocytes were less susceptible. We now show that mice deficient in the type I interferon (IFN) receptor were more resistant to Listeria infection and had less apoptotic lesions than wild-type counterparts. Furthermore, treatment of resting splenic lymphocytes with recombinant IFN-alphaA enhanced their susceptibility to LLO-induced apoptosis. Together, these data suggest that type I IFN signaling is detrimental to handling of a bacterial pathogen and may enhance the susceptibility of lymphocytes undergoing apoptosis in response to bacterial pore-forming toxins.

Animals↗

PubMed2002

Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection.

Interferons (IFNs) are essential for host defense. Although the antiviral effects of the type 1 IFNs IFN-alpha and IFN-beta (IFN-alpha/beta) have been established, their immunoregulatory functions, especially their ability to regulate IFN-gamma production, are poorly understood. Here we show that IFN-alpha/beta activate STAT4 directly (STAT, signal transducers and activators of transcription) and that this is required for IFN-gamma production during viral infections of mice, in concert with T cell receptor-derived signals. In contrast, STAT1 appears to negatively regulate IFN-alpha/beta induction of IFN-gamma. Thus, type 1 IFNs, in addition to interleukin-12, provide pathways for innate regulation of adaptive immunity, and their immunoregulatory functions are controlled by modulating the activity of individual STATs.

Animals↗

PubMed2004

Type I interferon genes from the egg-laying mammal, Tachyglossus aculeatus (short-beaked echidna).

The type I IFN are an important group of multifunctional cytokines that have, for whatever reason, evolved to a high level of complexity in eutherian mammals such as humans and mice. However, until recently, little was known about the type I IFN systems of the other two groups of extant mammals, the marsupials and the egg-laying monotremes. Preliminary partial type I IFN sequences from the short-beaked echidna were previously found to cluster only with the IFN-beta subtype in phylogenetic analyses, but a lack of sequence information made interpretation of these results tenuous. Here, we report cloning of the full-length genes of representatives from the two previously defined groups of echidna type I IFN by genomic walking PCR. Along with analysis of conserved cysteine placement and promoter elements, phylogenetic analysis incorporating these sequences strongly suggest that the two groups of echidna type I IFN genes are in fact homologous to IFN-alpha and IFN-beta, confirming that the duplication leading to these two major classes of type I IFN occurred prior to the divergence of eutherians and monotremes some 180 million years ago. Thus, even though there are major differences in gene copy number and heterogeneity, separate IFN-alpha and IFN-beta gene families are a feature of the cytokine networks of all three groups of living mammals.

Amino Acid Sequence↗

PubMed2006

Integrin alpha 11 is a novel type I interferon stimulated gene.

Interferons (IFNs) are a family of cytokines that have many biological functions in the cell, including regulation of cellular growth, differentiation, immunomodulation, and viral replication by inducing a set of interferon stimulated genes (ISGs). Based on their structure and biological activities IFNs are subdivided into two groups: type I IFNs, which includes IFN-alpha and IFN-beta and type II IFNs, represented by IFN-gamma. The aim of this work was to investigate whether integrin alpha 11 (ITGA-11), a novel collagen-binding integrin, is responsive to type I IFN treatment. Our findings indicated that type I IFNs were able to induce the ITGA-11 mRNA levels in T98G cells. Increased levels of ITGA-11 protein were also observed in IFN-treated cells. The in vivo induction of ITGA-11 was detected in spleen and lungs of IFN-treated BALB/c mice. T98G cells infected with Murine encephalomyocarditis virus showed increased levels of ITGA-11 mRNA and protein. We observed that the ITGA-11 promoter has binding sites for transcriptional factors regulated by IFNs and the double-stranded RNA dependent protein kinase (PKR). Therefore we investigated the role of PKR in the induction of ITGA-11 by using a PKR deficient mouse embryo fibroblast cell line (MEFs). PKR(-/-) MEFs treated with IFN did not show increased levels of ITGA-11 protein nor mRNA although that could be promptly detected in wild type MEFs. Taken together our data suggest that ITGA-11 is a new interferon stimulated gene.

Animals↗

PubMed1998

Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300.

It has been hypothesized that certain viral infections directly activate a transcription factor(s) which is responsible for the activation of genes encoding type I interferons (IFNs) and interferon-stimulated genes (ISGs) via interferon regulatory factor (IRF) motifs present in their respective promoters. These events trigger the activation of defense machinery against viruses. Here we demonstrate that IRF-3 transmits a virus-induced signal from the cytoplasm to the nucleus. In unstimulated cells, IRF-3 is present in its inactive form, restricted to the cytoplasm due to a continuous nuclear export mediated by nuclear export signal, and it exhibits few DNA-binding properties. Virus infection but not IFN treatment induces phosphorylation of IRF-3 on specific serine residues, thereby allowing it to complex with the co-activator CBP/p300 with simultaneous nuclear translocation and its specific DNA binding. We also show that a dominant-negative mutant of IRF-3 could inhibit virus-induced activation of chromosomal type I IFN genes and ISGs. These findings suggest that IRF-3 plays an important role in the virus-inducible primary activation of type I IFN and IFN-responsive genes.

Amino Acid Sequence↗

PubMed1995

Exogenous and endogenous type I interferons inhibit interferon-gamma-induced nitric oxide production and nitric oxide synthase expression in murine peritoneal macrophages.

We investigated the effect of type I IFNs (IFN-alpha and IFN-beta) on IFN-gamma-induced nitric oxide (NO) production by murine peritoneal macrophages. It was found that exogenous and also endogenous type I IFNs suppressed IFN-gamma-induced NO production, cytosolic inducible NO synthase (iNOS) activity, and iNOS mRNA accumulation in macrophages. Furthermore, we show here that type I IFNs prevent the NO-mediated deterioration of mitochondrial respiratory activity in macrophages. These results seem to indicate a possible protective role of type I IFNs against the NO-mediated immunosuppressive and/or cytotoxic effect of macrophages.

Animals↗

PubMed1999

Type I interferon is a powerful inhibitor of in vivo HIV-1 infection and preserves human CD4(+) T cells from virus-induced depletion in SCID mice transplanted with human cells.

Although several studies are available on the in vitro inhibitory activities of type I interferon (IFN) on HIV-1 replication, the role of these cytokines in the pathogenesis of AIDS is still matter of conjecture. Both beneficial and adverse effects have been envisaged and considered as a possible rationale for the development of either IFN or anti-IFN therapies in HIV-1-infected patients. In the present study, we have evaluated the efficacy of human type I IFN on HIV-1 infection and virus-induced depletion of human CD4 T cells in two models established in SCID mice. In SCID mice transplanted with human U937 cells (U937-SCID mouse model), continuous treatment with type I consensus IFN (CIFN) resulted in a total suppression of HIV-1 infection. This inhibitory effect was superior to that obtained after AZT treatments. Results from an ensemble of experiments in SCID mice transplanted with either control or genetically modified human U937 cells transduced with a Tat-inducible IFN-alpha gene (LTR-IFN-A2 U937) indicated that low levels of IFN-alpha, produced locally as a result of virus infection, were extremely effective in inhibiting acute HIV infection and virus replication. Of interest, LTR-IFN-A2 U937 cells conferred a strong anti-HIV-1 protection to coinjected bystander U937 cells. Notably, experiments with SCID mice reconstituted with human PBL (hu-PBL-SCID mouse model) showed that treatment with CIFN inhibited HIV-1 replication more effectively than AZT treatment. Remarkably, treatment with CIFN resulted in a clear-cut protection from the virus-induced depletion of human CD4 T cells, which was also associated with the generation of an antibody response toward HIV-1 antigens in 50% of the virus-injected xenografts. These results suggest that type I IFN efficiently preserves human CD4(+) cells from virus-induced damage in hu-PBL-SCID mice, not only by inducing an antiviral state in target cells but also by stimulating anti-HIV-1 human immune responses in vivo.

Animals↗

PubMed1994

Suppression of relapsing experimental autoimmune encephalomyelitis in the SJL/J mouse by oral administration of type I interferons.

We induced a chronic relapsing form of experimental autoimmune encephalomyelitis in 7- to 10-week-old female SJL/J mice using a subcutaneous injection of an emulsion containing syngeneic mouse spinal cord homogenate in phosphate-buffered saline and Mycobacterium tuberculosis (MT) in incomplete Freund's adjuvant. Following the animals' recovery from the first attack periods, we fed them varying doses of type I interferon (IFN) or mock IFN three times per week for 6 weeks. This treatment decreased proliferation to guinea pig myelin basic protein and MT compared with control in draining lymph node and diminished inflammation in the CNS. Oral IFN altered the cytokine profile of concanavalin A-activated spleen cells by decreasing IFN-gamma secretion. These results suggest that type I IFNs are active by the oral route, have significant clinical and immunomodulatory effects, and can decrease an established and ongoing immune response to sensitized antigens. The oral administration of biologic-response modifiers, such as type I IFNs, provides a potentially nontoxic, convenient, continuous means of delivering immunoactive substances via the gut regional immune system that can alter cytokine production and suppress clinical relapses.

Administration, Oral↗

PubMed1981

Treatment of NZB/NZW F1 hybrid mice with Mycobacterium bovis strain BCG or type II interferon preparations accelerates autoimmune disease.

NZB/NZW F1 hybrid mice develop a spontaneous autoimmune disease characterized by the appearance of antinuclear antibodies and premature death due to immune complex glomerulonephritis. To investigate the possible effects of cellular immune stimulation on this disorder, groups of female NZB/NZW mice, aged 2, 5, and 7 months, were treated either with the nonspecific immunostimulatory agent Mycobacterium bovis strain BCG or with saline. Mice treated with BCG at ages 5 and 7 months died sooner than age-matched controls, and death was associated with severe glomerulonephritis, suggesting that BCG may have accelerated autoimmunity in these mice. Since BCG is known to stimulate the production of type II (or gamma) interferon, a substance with potent immunoregulatory effects, a second study was carried out to assess the effects of type II interferon on NZB/NZW disease. A greater number of type II interferon-treated mice died by 9 months of age when compared to controls, and the increased death rate was associated with a more rapid development of antinuclear antibodies and histologically confirmed glomerulonephritis. These data, together with a recent report of increases in the level of serum type II interferon in patients with active systemic lupus erythematosus, suggest that type II interferon may play a role in the pathogenesis of autoimmune disease.

Animals↗

PubMed2002

The natural alliance between type I interferon and dendritic cells and its role in linking innate and adaptive immunity.

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) and thus play a pivotal role in induction of the immune response. Recent studies in both human and mouse models have shown that type I IFN, cytokines originally characterized for their antiviral activity and exerting multiple biologic effects, efficiently promote the differentiation and activation of DCs. These observations, together with the findings that DCs can express biologically relevant levels of type I interferon (IFN) and, in particular, that high amounts of these cytokines are released by specialized DC precursors (i.e., plasmacytoid DCs) in response to viral infections, strongly suggest the existence of a natural alliance between type I IFN and DCs, which is instrumental in ensuring an efficient immune response to both infectious agents and tumors. Further recent knowledge on the interactions between type I IFN and DCs emphasizes the importance of these cytokines in linking innate and adaptive immunity and may lead to new perspectives in their use as vaccine adjuvants as well as in strategies for the development of DC-based vaccines.

Animals↗

PubMed1996

Essential and non-redundant roles of p48 (ISGF3 gamma) and IRF-1 in both type I and type II interferon responses, as revealed by gene targeting studies.

BACKGROUND: Interferons (IFNs) are a class of cytokines which confer cellular resistance against viral infections. Type I (IFN-alpha and -beta) and type II (IFN-gamma) IFNs utilize distinct receptors, the stimulation of which results in the induction of downstream target genes. These target genes usually contain within their promoter region an IFN responsive element, termed ISRE (IFN stimulated response element) which binds a heterotrimeric transcription factor, ISGF3 (IFN-stimulated gene factor 3) consisting of p48 (ISGF3 gamma), Stat1 (Signal transducers and activators of transcription-1; alpha or beta), and Stat2. The ISRE sequence overlaps with that of IRF-E which binds another IFN-inducible factor, IRF-1 (IFN regulatory factor-1). RESULTS: We generated mice lacking p48 by gene targeting. We show that p48 plays an essential role in both type I and type II IFN responses; activation of IFN-inducible genes and establishment of the antiviral state by IFN-alpha or -gamma are both severely impaired, and ISRE-binding activities induced by both IFNs are absent in the p48-negative embryonic fibroblasts (EFs). Furthermore, we generated mice deficient for both p48 and IRF-1 and found that at least one IFN-inducible gene is dependent on both factors. CONCLUSIONS: p48 and IRF-1 do not perform redundant functions in the cell, but rather complement one another in both type I and II IFN responses.

Animals↗

PubMed1995

Transmembrane signaling by the alpha subunit of the type I interferon receptor is essential for activation of the JAK kinases and the transcriptional factor ISGF3.

The Type I interferon (IFN) receptor has a multisubunit structure. The component of the receptor that has been most thoroughly studied is the alpha subunit. Expression of the alpha subunit in mouse L-929 cells confers antiviral response to human IFN alpha 8, but not to human IFN alpha 2 or IFN beta. This antiviral effect is observed without a significant increase in IFN binding. It has not been determined why mouse cells expressing the human alpha subunit show different response to the antiviral activity of distinct human Type I IFNs. In this report, we demonstrate that the response to human Type I IFNs in mouse cells expressing the alpha subunit is dependent on cross-binding to the mouse receptor. This is supported by the finding that human IFN alpha 8, but not human IFN alpha 2, cross-binds to the mouse receptor even in the absence of expression of the human alpha subunit. We also demonstrate that only mouse cells expressing the human alpha subunit are able to tyrosine-phosphorylate p135tyk2 and JAK-1 and to form the ISGF3 complex in response to human IFN alpha 8. These results demonstrate that the alpha subunit is essential for IFN alpha signaling through the JAK kinases and ISGF3.

Animals↗

PubMed2006

Autocrine type I interferon amplifies dendritic cell responses to lipopolysaccharide via the nuclear factor-kappaB/p38 pathways.

The central role of dendritic cells (DC) in the initiation of immune responses requires these cells to be able to determine the degree of danger in their microenvironment. Abrogating the activity of type I interferon (IFN) secreted after lipopolysaccharide (LPS) stimulation of DC inhibits CD86 and human leucocyte antigen-DR (HLA-DR) upregulation at a low LPS concentration. At a higher concentration of LPS, while changes in surface phenotype are not dependent on type I IFN, this cytokine is required for maximal secretion of interleukin-12 (IL-12) and tumour necrosis factor-alpha (TNFalpha) by DC. Thus, the secretion and autocrine activity of type I IFN after Toll-like receptor stimulation enables DC to orchestrate a hierarchical maturation response with regard to changes in surface phenotype and secretion of cytokines. In addition, the activation of nuclear factor-kappaB and p38 pathways in DC can occur either in an additive fashion when DC are exposed to dual stimulation or can be activated in discrete phases over time when DC are exposed to LPS alone. The differential activation of these pathways provides a mechanism for DC to integrate the activation by multiple stimuli and thus amplify responses to pathogen infection.

B7-2 Antigen↗

PubMed2006

Direct application of plasmid DNA containing type I interferon transgenes to vaginal mucosa inhibits HSV-2 mediated mortality.

The application of naked DNA containing type I interferon (IFN) transgenes is a promising potential therapeutic approach for controlling chronic viral infections. Herein, we detail the application of this approach that has been extensively used to restrain ocular HSV-1 infection, for antagonizing vaginal HSV-2 infection. We show that application of IFN-alpha1, -alpha5, and -beta transgenes to vaginal mouse lumen 24 hours prior to HSV-2 infection reduces HSV-2 mediated mortality by 2.5 to 3-fold. However, other type I IFN transgenes (IFN- alpha4, -alpha5, -alpha6, and -alpha9) are non effectual against HSV-2. We further show that the efficacy of IFN-alpha1 transgene treatment is independent of CD4+ T lymphocytes. However, in mice depleted of CD8+ T lymphocytes, the ability of IFN-alpha1 transgene treatment to antagonize HSV-2 was lost.

Journal Article↗

PubMed2003

Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice.

Indirect evidence suggests that type-I interferons (IFN-alpha/beta) play a significant role in the pathogenesis of lupus. To directly examine the contribution of these pleiotropic molecules, we created congenic NZB mice lacking the alpha-chain of IFN-alpha/betaR, the common receptor for the multiple IFN-alpha/beta species. Compared with littermate controls, homozygous IFN-alpha/betaR-deleted NZB mice had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease, and mortality. These reductions were intermediate in the heterozygous-deleted mice. The disease-ameliorating effects were accompanied by reductions in splenomegaly and in several immune cell subsets, including B-1 cells, the major producers of anti-erythrocyte autoantibodies. Decreases of B and T cell proliferation in vitro and in vivo, and of dendritic cell maturation and T cell stimulatory activity in vitro were also detected. Absence of signaling through the IFN-alpha/betaR, however, did not affect increased basal levels of the IFN-responsive p202 phosphoprotein, encoded by a polymorphic variant of the Ifi202 gene associated with the Nba2 predisposing locus in NZB mice. The data indicate that type-I IFNs are important mediators in the pathogenesis of murine lupus, and that reducing their activity in the human counterpart may be beneficial.

Animals↗