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At least 181 records · Page 10Linked to original sources
PubMed2006

Exhaustion of type I interferon response following an acute viral infection.

Viral infections often cause a period of heightened susceptibility to a secondary infection but the cause of this phenomenon is unknown. We found that a primary viral infection in mice rapidly triggers an IFN-I-dependent partial activation state in the majority of B and T lymphocytes, which reverts to a resting phenotype within 5 days. When a secondary infection with an unrelated virus occurred 5 to 9 days after the primary infection, no recurrence of marked activation of lymphocytes was observed. This was not due to an inherent inability of the previously activated cells to undergo renewed partial activation, because they responded when challenged with virus after transfer into "naive" recipients. Instead, the failure to respond optimally resided in the original host's incapacity to mount an IFN-I response to the secondary infection during this time period. Thus, transient immunosuppression through exhaustion of IFN-I production during an acute viral infection creates a time period of enhanced susceptibility to secondary infection.

Acute Disease↗
PubMed1991

Enhanced expression of heat shock protein and mRNA synthesis by type I interferon in human HL-60 leukemic cells.

The effects of IFN and mild hyperthermia on the responses of human promyelocytic HL-60 cells were investigated. Cells subjected to an elevated culture temperature (39.5 degrees-40.5 degrees C instead of 37 degrees C, herein referred to as heat-treated cells) showed an increase in heat shock proteins (HSPs) and corresponding mRNA synthesis, which were additionally potentiated by the presence of IFN. With cells cultured at 37 degrees C, IFN had no effect on HSP expression. The observed inhibition (40-70%) of RNA polymerase II-directed RNA synthesis (based on alpha-amanitin sensitivity) in isolated nuclei of heat-treated cells was also significantly reversed by the simultaneous addition of IFN. These data suggest that the IFN-amplified HSP gene expression may be involved in preventing irreversible damage or in fine tuning the recovery of mammalian cells from heat stress.

Cell Nucleus↗
PubMedDate not supplied

[Production of type I interferons in the body exposed to yeast RNA-tiloron molecular complexes].

Molecular complexes forming as a result of interaction between yeast RNA preparations with 2,7-bis[-(diethylaminoethoxy)-fluorene]-9-on dihydrochloride (tilorone) administered parenterally to mice cause the appearance of interferon in high titers compatible to those induced by standard inductors of polyribonucleotide origin, poly(I)-poly(C) and larifan. Some physiologic conditions of interferonogenesis have been studied. The above molecular complexes in the dose range used experimentally were completely nontoxic. Hence, these complexes are promising agents for interferon induction.

Animals↗
PubMed2000

Antibody-dependent induction of type I interferons by poliovirus in human mononuclear blood cells requires the type II fcgamma receptor (CD32).

The induction of type I interferons (IFNs) in peripheral blood mononuclear cells (PBMCs) can be triggered by viral infection or exposure to viral glycoproteins. Here we show that the IFN-alpha-inducing capacity of attenuated poliovirus vaccine strains is dramatically enhanced in the presence of human polyvalent immunoglobulin G (IgG). The transcription of both IFN-alpha and IFN-beta genes was detected by RT-PCR in stimulated cells. This antibody-dependent activation of type I IFNs genes was also observed with Formalin-inactivated or UV-inactivated poliovirus, but not with empty poliovirus capsids. The ability of poliovirus-antibody complexes to induce IFN-alpha was specifically inhibited when PBMCs were preincubated with an excess of the Fc fragment of IgG. Monoclonal antibodies directed to FcgammaRII (CD32) were also inhibitory, whereas antibodies to the two other classes of Fcgamma receptors, CD16 and CD64, were not. Also, aggregation of FcgammaRII by anti-CD32 antibodies alone failed to induce IFN-alpha production. Our results suggest that induction of type I interferons by poliovirus-antibody complexes depends on CD32-mediated phagocytosis of RNA-containing viral particles. As suggested by the results of an ELISPOT analysis, only a fraction of the IFN-alpha-producing cells are able to synthesize IFN-alpha in response to poliovirus-IgG complexes.

Antibodies, Viral↗
PubMed2002

Genetic basis of patients with bacille Calmette-Guérin osteomyelitis in Japan: identification of dominant partial interferon-gamma receptor 1 deficiency as a predominant type.

Interferon (IFN)-gamma-mediated immunity plays an important role in host defense against intracellular pathogens, especially mycobacteria. Six Japanese children with bacille Calmette-Guérin (BCG) osteomyelitis were evaluated (1 disseminated, 3 multiple, and 2 solitary types) for mutations of genes involved in interleukin-12-dependent, IFN-gamma-mediated immunity. Heterozygous small deletions with frameshift (818del4 and 811del4) that are consistent with the diagnosis of partial dominant IFN-gamma receptor 1 (IFN-gammaR1) deficiency were detected in 3 unrelated patients. Expression of IFN-gammaR1 on monocytes was significantly increased in all 3 patients. Screening of family members with recurrent and disseminated mycobacterial infections found the identical deletion in 1 of the fathers. Antimycobacterial treatment was effective in these patients and resulted in good clinical outcome. This study demonstrated that partial dominant IFN-gammaR1 deficiency was the most common in Japanese patients who showed predisposition to curable BCG osteomyelitis.

Adult↗
PubMed1995

Atypical spI interferon binds on porcine cells to a major component of type I interferon receptor.

The short porcine type I interferon (spI IFN), encoded by a gene physiologically expressed by the pig embryonic trophoblast during implantation, represents the first member of a novel family type I IFN. Binding and cross-linking experiments were carried out to characterize its cellular receptor. On porcine kidney cells, specific binding of 125I-spI IFN could be displaced significantly by spI IFN, rpIFN-alpha 1, and rhIFN-alpha 1, but not by rhIFN-alpha 2a or by rpIFN-gamma. On the other hand, all these type I IFNs but not rpIFN-gamma were capable of displacing bound 32P-hIFN-alpha A-P1 on these cells. Cross-linking data show that the specific 120 kD complex formed with these two radiolabeled ligands was displaceable by an excess of both spI IFN and rpIFN-alpha 1. These results provide primary evidence that spI IFN shares at least the major binding subunit of type I IFN receptor on porcine cells. On human WISH cells, 125I-spI IFN did not form any complex, nor did spI IFN affect cross-linking complexes of 32P-hIFN-alpha A-P1 on these cells, unlike rpIFN-alpha 1. The lack of antiviral and antiproliferative effects of spI IFN on human cells is primarily a result of its inability to recognize human type I IFN receptor.

Animals↗
PubMed2006

Neurons produce type I interferon during viral encephalitis.

Type I interferons, also referred to as IFN-alpha/beta, form the first line of defense against viral infections. Major IFN-alpha/beta producers in the periphery are the plasmacytoid dendritic cells (pDCs). Constitutive expression of the IFN regulatory factor (IRF)-7 enables pDCs to rapidly synthesize large amounts of IFN-alpha/beta after viral infection. In the central nervous system (CNS), pDCs are considered to be absent from the parenchyma, and little is known about the cells producing IFN-alpha/beta. The study presented here aimed to identify the cells producing IFN-alpha/beta in the CNS in vivo after infection by neurotropic viruses such as Theiler's virus and La Crosse virus. No cells with high constitutive expression of IRF-7 were detected in the CNS of uninfected mice, suggesting the absence of cells equivalent to pDCs. Upon viral infection, IFN-beta and some subtypes of IFN-alpha, but not IFN-epsilon or IFN-kappa, were transcriptionally up-regulated. IFN-alpha/beta was predominantly produced by scattered parenchymal cells and much less by cells of inflammatory foci. Interestingly, in addition to some macrophages and ependymal cells, neurons turned out to be important producers of both IFN-alpha and IFN-beta. However, only 3% of the infected neurons produced IFN-alpha/beta, suggesting that some restriction to IFN-alpha/beta production existed in these cells. All CNS cell types analyzed, including neurons, were able to respond to type I IFN by producing Mx or IRF-7. Our data show that, in vivo, neurons take an active part to the antiviral defense by being both IFN-alpha/beta producers and responders.

Animals↗
PubMed1995

Modification of acute experimental autoimmune encephalomyelitis in the Lewis rat by oral administration of type 1 interferons.

The effect of orally administered type 1 interferons on the severity of acute experimental autoimmune encephalomyelitis (EAE), a T cell-mediated autoimmune disease, was examined by inoculation of Lewis rats with guinea pig myelin basic protein (GPMBP) and complete Freund's adjuvant. Rats were fed either rat species-specific or human recombinant type 1 interferon (IFN) or mock IFN daily for 7 days preceding immunization and for 21 days thereafter. There was a significant decrease in the clinical score and inflammatory foci in animals fed 5000 units IFN compared with mock-treated animals. There was a significant decrease in clinical score and number of inflammatory foci in spinal cord in animals fed orally 5000 units human recombinant IFN-alpha PO compared with SC 5000 units recombinant human IFN-alpha. Oral administration of type 1 interferon, as opposed to subcutaneous administration, inhibited the secretion of IFN-gamma from ConA-activated draining popliteal lymph node cells compared with mock-fed animals. These experiments demonstrate that acute EAE is more effectively inhibited by equivalent amounts of orally in contrast to parenterally administered IFN-alpha. These results suggest that type 1 IFNs are active by the oral route and have significant clinical and histologic effects in acute autoimmune disease.

Administration, Oral↗
PubMed1992

Dissection of the interferon gamma-MHC class II signal transduction pathway reveals that type I and type II interferon systems share common signalling component(s).

We have used a herpes virus thymidine kinase (HSV-TK) based metabolic selection system to isolate mutants defective in the interferon gamma mediated induction of the MHC class II promoter. All the mutations act in trans and result in no detectable induction of MHC and invariant chain (Ii) gene expression. Scatchard analysis indicates that the mutants have a normal number of surface IFN gamma receptors with the same affinity constant. The mutants fall into two broad categories. One class of mutants is still able to induce MHC class I, IRF-1, 9-27, 1-8 and GBP genes by IFN gamma. A second class of mutants is defective for the IFN gamma induction of all the genes tested; surprisingly, the IFN alpha/beta induction of MHC class I, 9-27, ISG54 and ISG15 genes is also defective in these mutants, although different members of this class can be discriminated by the response of the GBP and IRF-1 genes to type I interferons. These data demonstrate that the signalling pathways of both type I and type II interferon systems share common signal transduction component(s). These mutants will be useful for the study of IFN gamma regulation of class II genes and Ii chain, and to elucidate molecular components of type I and type II interferon signal transduction.

Base Sequence↗
PubMed1998

Mapping human interferon-alpha (IFN-alpha 2) binding determinants of the type I interferon receptor subunit IFNAR-1 with human/bovine IFNAR-1 chimeras.

Type I interferons bind to a common receptor (IFNAR), composed of two transmembrane polypeptides, IFNAR-1 and IFNAR-2. Although human IFNAR-1 has a weak intrinsic affinity for human Type I interferons (IFNs), bovine IFNAR-1 binds human Type I IFNs with moderate (nM) affinity, and can be conveniently used to investigate the regions of IFNAR-1 involved in ligand binding. We have constructed 14 bovine/human IFNAR-1 chimeras by exchanging homologous subdomains in the extracellular portion of the receptor. These chimeras were expressed at very high levels on COS cells, and their ability to bind HuIFN-alpha2 was measured. No single bovine subdomain substituted into human IFNAR-1 could confer moderate-affinity ligand binding on the resulting chimera. Simultaneous substitution of bovine IFNAR-1 subdomains 2 and 3 for the homologous human subdomains resulted in a dramatic increase in the binding of IFN-alpha2, suggesting that critical determinants for moderate-affinity ligand binding by BoIFNAR-1 reside in these two subdomains. Bovine subdomains 1 and/or 4 each further enhanced IFN-alpha2 binding in the presence of bovine subdomains 2 and 3. Thus, the binding interactions of BoIFNAR-1 with IFNs appears to be more complex than that of other class II cytokine receptors with their ligands.

Animals↗
PubMed1994

Human type I interferons: structure and function.

Human type I interferons (IFNs) comprise a family of 13 IFN-alpha subtypes and single species of IFN-beta and IFN-omega. Their 20% overall sequence homology determines identical secondary and tertiary folding of polypeptides. Three-dimensional models suggest that the globular structure of type I IFNs consists of a bundle of 5 alpha-helices, which might form two polypeptide domains. Disulfide bond Cys 29-Cys 139 stabilizes both domains in a bioactive configuration. The IFN molecule exerts its functional entity only as an organic polypeptide complex and therefore molecular fragments apparently lack biological activity. IFN-beta, IFN-omega and some IFN-alpha subtypes are glycoproteins, but the sugar moiety was found to be neither structurally nor functionally relevant. Type I IFNs share a common cellular receptor, a fact that implies a high structural conservativity of their receptor-binding areas. Two conservative hydrophilic regions associated with the amino acids (aa) 30-41 and 120-145 appear to constitute the basic framework of receptor recognition site in type I IFNs. However, the individual IFN-(sub)types induce different spectra of biological effects which reflect some specificity in modelling of binding sites. Besides a subtle sequential heterogeneity in the segments aa 30-41 and 120-145, also the variable hydrophilic aa regions 23-26, 68-85 and 112-121 are responsible for structural and functional individuality among human type I IFNs. The interaction between IFN and its receptor seems to be a complex event which triggers simultaneously antiviral, antiproliferative and immunomodulating actions, although different parts of IFN molecule are not involved equally in eliciting of respective basal activities.

Amino Acid Sequence↗