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PubMed2002

Signal transduction by type I interferons.

The two classes of interferons, type I (IFNalpha, IFNbeta, IFNomega, and IFNtau) and type II (IFNgamma) are pleiotropic cytokines that exhibit antiviral, antiproliferative, and immunomodulatory effects on their target cells. This article summarizes the advances made in elucidating the molecular events that mediate the biological responses to type I interferons.

Active Transport, Cell Nucleus↗
PubMed1980

A family of structural genes for human lymphoblastoid (leukocyte-type) interferon.

Amino acid sequences of tryptic and chymotryptic peptides from human lymphoblastoid interferon (IFN-alpha) have been determined. The results show that IFN-alpha consists of a family of proteins with at least five different, but homologous, primary structures. There appears to be little, if any, glycosylation of the major components of IFN-alpha.

Amino Acid Sequence↗
PubMed1987

Immunoferon (AM3) enhances the activities of early-type interferon inducers and natural killer cells.

The "in vivo" effect of Immunoferon (AM3) on the production of interferon (IFN) and natural killer (NK) activity in young and old mice was studied. Although AM3 is not an IFN inducer by itself, enhancements in the serum IFN levels were produced when drug was associated to Newcastle disease virus or bacterial lipopolysaccharides as IFN inducers. This effect appeared to be dependent on the time lapsed between the inducer agent and drug. In addition, a significant stimulating effect on NK cell activity was also produced by AM3 treatments. This effect could be a consequence of a marked IFN induction and/or a modifying effect in prostaglandin synthesis.

Animals↗
PubMedDate not supplied

[Monoclonal antibodies to natural human gamma-type interferon].

Nine hybridomas producing monoclonal antibodies (MCA) to natural human gamma interferon (IF-gamma) were generated. BALB/c mice were immunized with nonpurified IF-gamma preparation synthesized by lymphoid cells of the peripheral blood of donors in response to induction with staphylococcal enterotoxin A. For the first time somatic hybridization was done with the use of a medium with a high content of HEPES which maintained hybridomas viable for a long period of time. Out of 9 hybridomas, two (-gamma 6.1 and gamma-8.1) were shown to produce MCA with a high binding activity in the enzyme immunoassay. The same MCA effectively neutralized the biological activity of natural IF-gamma.

Animals↗
PubMed1995

Type I and type II interferons upregulate functional type I interleukin-1 receptor in a human fibroblast cell line TIG-1.

The regulation of type I interleukin-1 receptor (IL-1R) expression by type I, interferon (IFN)-alpha A/D, and type II IFN, IFN-gamma, in a human fibroblast cell line TIG-1 was investigated. After 2 h stimulation with human IFN-alpha A/D or IFN-gamma, the levels of type I IL-1R mRNA increased. We previously reported that IL-1 upregulates transcription and cell surface molecules of type I IL-1R in TIG-1 cells through induction of prostaglandin (PG) E2 and cAMP accumulation. However, indomethacin was unable to inhibit the effect of IFNs, indicating that IFNs augment IL-1R expression through a pathway distinct from that of IL-1. The augmentation was also observed in other fibroblast cell lines. Nuclear run-on assays and studies of the stability of mRNA suggested that the increase in IL-1R mRNA was a result of the enhanced transcription of IL-1R gene. Binding studies using 125I-IL-1 alpha revealed that the number of cell surface IL-1R increased with no change in binding affinity by treatment with these IFNs. Pretreatment of the cells with IFNs enhanced IL-1-induced IL-6 production, indicating that IFNs upregulate functional IL-1R. IL-1 and IFNs are produced by the same cell types, as well as by the adjacent different cell types, and are concomitantly present in lesions of immune and inflammatory reactions. These results therefore suggest that IFNs exhibit synergistic effects with IL-1 through upregulation of IL-1R. Augmented production of IL-6 may also contribute to the reactions.

Cell Line↗
PubMed2001

Down-modulation of type 1 interferon responses by receptor cross-competition for a shared Jak kinase.

In contrast to the large number of class I and II cytokine receptors, only four Janus kinase (Jak) proteins are expressed in mammalian cells, implying the shared use of these kinases by many different receptor complexes. Consequently, if receptor numbers exceed the amount of available Jak, cross-interference patterns can be expected. We have engineered two model cellular systems expressing two different exogenous Tyk2-interacting receptors. A receptor chimera was generated wherein the extracellular part of the interferon type 1 receptor (Ifnar1) component of the interferon-alpha/beta receptor is replaced by the equivalent domain of the erythropoietin receptor. Despite Tyk2 activation, erythropoietin treatment of cells expressing this erythropoietin receptor/Ifnar1 chimera did not evoke any detectable IFN-type response. However, a dose-dependent interference with signal transduction via the endogenous Ifnar complex was found for STAT1, STAT2, STAT3, Tyk2, and Jak1 activation, for gene induction, and for antiviral activity. In a similar approach, cells expressing the beta1 chain of the interleukin-12 receptor showed a reduced transcriptional response to IFN-alpha as well as reduced STAT and kinase activation. In both model systems, titration of the Tyk2 kinase away from the Ifnar1 receptor chain accounts for the observed cross-interference.

Animals↗
PubMed2003

The C protein of measles virus inhibits the type I interferon response.

Type I interferons (IFNalpha/beta) are an important part of innate immunity to viral infections because they induce an antiviral response and limit viral replication until the adaptive response clears the infection. Since the nonstructural proteins of several paramyxoviruses inhibit the IFNalpha/beta response, we chose to explore the role of the C protein of measles virus (MV) in such inhibition. Previous studies have suggested that the MV C protein may serve as a virulence factor, but its role in the pathogenesis of MV remains undefined. In the present study, a recombinant MV strain that does not express the C protein (MV C-) and its parental strain (Ed Tag) were used. Growth of MV C- was restricted in human peripheral blood mononuclear cells and HeLa cells, but in the presence of neutralizing antibodies to IFNalpha/beta, MV C- produced titers that were equivalent to those of Ed Tag. In addition, expression of the MV C protein from plasmid DNA inhibited the production of an IFNalpha/beta responsive reporter gene and, to a lesser extent, inhibited an IFNgamma responsive reporter gene. The ability of the MV C protein to suppress the IFNalpha/beta response was confirmed using a biologic assay. After IFNbeta stimulation, HeLa cells infected with Ed Tag produced five-fold less IFNalpha/beta than cells infected with MV C-. While the mechanism of inhibition remains unclear, these data suggest that the MV C protein plays an important role in the pathogenesis of MV by inhibiting IFNalpha/beta signaling.

DNA-Binding Proteins↗
PubMed2005

IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction.

Type I interferons are central mediators for antiviral responses. Using high-throughput functional screening of interferon inducers, we have identified here a molecule we call interferon-beta promoter stimulator 1 (IPS-1). Overexpression of IPS-1 induced type I interferon and interferon-inducible genes through activation of IRF3, IRF7 and NF-kappaB transcription factors. TBK1 and IKKi protein kinases were required for the IPS-1-mediated interferon induction. IPS-1 contained an N-terminal CARD-like structure that mediated interaction with the CARD of RIG-I and Mda5, which are cytoplasmic RNA helicases that sense viral infection. 'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection. Thus, IPS-1 is an adaptor involved in RIG-I- and Mda5-mediated antiviral immune responses.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Type 1 interferon (IFNalpha/beta) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite.

Type 2 nitric oxide synthase (NOS2) is required for the Th1-dependent healing of infections with intracellular microbes, including Leishmania major. Here, we demonstrate the expression and define the function of NOS2 during the innate response to L. major. At day 1 of infection, genetic deletion or functional inactivation of NOS2 abolished the IFNgamma and natural killer cell response, increased the expression of TGFbeta, and caused parasite spreading from the skin and lymph node to the spleen, liver, bone marrow, and lung. Induction of NOS2 was dependent on IFNalpha/beta. Neutralization of IFNalpha/beta mimicked the phenotype of NOS2-/- mice. Thus, IFNalpha/beta and NOS2 are critical regulators of the innate response to L. major.

Animals↗
PubMed1994

A gene on human chromosome 21 located in the region 21q22.2 to 21q22.3 encodes a factor necessary for signal transduction and antiviral response to type I interferons.

The type I interferons (IFNs) are a family of multifunctional cytokines which includes the 15 IFN alpha subtypes and IFN beta. These IFNs compete for binding to cell surface receptors. However, murine cells transfected with a cDNA for a human IFN alpha receptor (IFNAR) developed an antiviral response only to human IFN alpha B, but not to human IFN alpha 2 nor -beta(1). In this study we show, using a panel of CHO-human chromosome 21 hybrid cell lines which all express IFNAR, that only those containing the region 21q22.2 to 21q22.3 transduce signals for IFN responses. Two such hybrid cell lines responded to IFNs alpha 2, -alpha B and -beta by induction of 2'-5' oligoadenylate synthetase and resistance to viral infection. Other hybrid cell lines, that lacked the region 21q22.2-3, failed to transduce signals as above; even though they expressed IFNAR and bound human IFN alpha 2, -alpha B, and -beta. These data demonstrate that a gene(s) located in the region 21q22.2-3 encodes a factor(s) which is necessary for signaling but does not influence ligand binding. This factor is not the cofactor required for IFN gamma signaling which is located in the region 21p to 21q22.1(2).

2',5'-Oligoadenylate Synthetase↗