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Results for “Type I interferon”

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PubMed1987

High-affinity binding sites for human 26-kDa protein (interleukin 6, B cell stimulatory factor-2, human hybridoma plasmacytoma growth factor, interferon-beta 2), different from those of type I interferon (alpha, beta), on lymphoblastoid cells.

The human 26-kDa glycoprotein (26K) is a cytokine produced by lymphoid as well as nonlymphoid cells. So far it is active as (a) a potent hybridoma and plasmacytoma growth factor on mouse cells, (b) a B cell differentiating factor on human cells, and (c) (for some authors) an interferon (IFN). Internally labeled recombinant human 26K, obtained by translation of mRNA in Xenopus oocytes, was used to investigate the presence of specific receptors for this new cytokine and to analyze its binding to responsive cells. The results indicate that (a) the 26K-responsive human lymphoblastoid CESS cells express about 1500 high-affinity (Kd = 30 pM) binding sites for this cytokine, (b) this binding is not competed for by interleukin (IL)1, IL2, tumor necrosis factor (TNF), IFN-alpha 2, IFN-beta or IFN-gamma, and (c) these 26K-binding sites are different from the classical type I (alpha-beta) IFN receptors by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Binding Sites↗

PubMed1995

Immune defence in mice lacking type I and/or type II interferon receptors.

Mice lacking the receptor for type I interferon (IFN-alpha beta, A129 mice), for type II interferon (IFN-gamma, G129 mice) or for both receptors (AG129 mice) have been generated by embryonic stem cell mediated gene targeting and inter-crossing A129 x G129, respectively. The role of the two IFN systems in controlling a range of infections has been studied using these mice. Type I IFN is shown to be responsible for the immune defence against most viral infections tested (Lymphocytic Choriomeningitis Virus, Semliki Forest Virus, Theiler's Virus, Vesicular Stomatitis Virus), type II IFN seems to be of little importance. In Vaccinia Virus and Theiler's Virus infection, however, both IFN systems were found to play a nonredundant role. IFN-gamma was critical for the defence against intracellular bacteria (Mycobacterium, Listeria) and parasites (Leishmania), whereas IFN-alpha beta was not. IFN-alpha beta is produced by virus-infected cells within hours and plays an important role in preventing virus spread early. Production of IFN-gamma on the other hand needs activation of the immune system and plays a major role later, i.e. mostly during the immune response. Data obtained with the mice described here show that both IFN systems seem to have evolved to complement each other in the host defence against a wide variety of infectious agents.

Animals↗

PubMed2004

Disruption of Erk-dependent type I interferon induction breaks the myxoma virus species barrier.

Myxoma virus, a member of the poxvirus family, causes lethal infection only in rabbits, but the mechanism underlying the strict myxoma virus species barrier is not known. Here we show that myxoma virus infection of primary mouse embryo fibroblasts elicited extracellular signal-regulated kinase (Erk) signaling, which was integrated to interferon regulatory factor 3 activation and type I interferon induction. We further show that Erk inactivation or disruption of interferon signaling mediated by the transcription factor STAT1 broke the cellular blockade to myxoma virus multiplication. Moreover, STAT1 deficiency rendered mice highly susceptible to lethal myxoma virus infection. Thus, the Erk-interferon-STAT1 signaling cascade elicited by myxoma virus in nonpermissive primary mouse embryo fibroblasts mediates an innate cellular barrier to poxvirus infection.

Animals↗

PubMed1998

Differences in activity between alpha and beta type I interferons explored by mutational analysis.

Type I interferon (IFN) subtypes alpha and beta share a common multicomponent, cell surface receptor and elicit a similar range of biological responses, including antiviral, antiproliferative, and immunomodulatory activities. However, alpha and beta IFNs exhibit key differences in several biological properties. For example, IFN-beta, but not IFN-alpha, induces the association of tyrosine-phosphorylated receptor components ifnar1 and ifnar2, and has activity in cells lacking the IFN receptor-associated, Janus kinase tyk2. To define the structural basis for these functional differences we produced human IFN-beta with point mutations and compared them to wild-type IFN-beta in assays that distinguish alpha and beta IFN subtypes. IFN-beta mutants with charged residues (N86K, N86E, or Y92D) introduced at two positions in the C helix lost the ability to induce the association of tyrosine-phosphorylated receptor chains and had reduced activity on tyk2-deficient cells. The combination of negatively charged residues N86E and Y92D (homologous with IFN-alpha8) increased the cross-species activity of the mutant IFN-betas on bovine cells to a level comparable to that of human IFN-alphas. In contrast, point mutations in the AB loop and D helix had no significant effect on these subtype-specific activities. A subset of these latter mutations did, however, reduce activity in a manner analogous to IFN-alpha mutations. The effects of these mutations on IFN-beta activity are discussed in the context of a family of related ligands acting through a common receptor and signaling pathway.

Amino Acid Sequence↗

PubMed2006

Bupleurum kaoi inhibits Coxsackie B virus type 1 infection of CCFS-1 cells by induction of type I interferons expression.

Coxsackie B virus type 1 (CVB1) infection is known to cause high morbidity and mortality in children, however, there is no effective drug for treating this disease. The present study aimed to examine the antiviral activity of Bupleurum kaoi (BK), a popular herbal drug for treating viral and bacterial infections, against CVB1 infection and its mechanisms of action. Our data showed that BK neutralized the CVB1-induced cytopathic effect in human neonatal foreskin fibroblast cell line (CCFS-1/KMC), with IC50 and EC50 values around 12.38 microg/ml and 50.93 microg/ml, respectively. Its CC50 and SI values were 883.56 microg/ml and 17.34, respectively. These results suggest that BK possessed anti-CVB1 activity, and showed no effect on CCFS-1 cell viability and growth at concentration 250 microg/ml. The time-of-addition studies showed that BK (50, 100 and 200 microg/ml) added at various time of preinfection (-1 to -3 h), coinfection (0 h) and postinfection (1-3 h) could inhibit CVB1 infection. Interestingly, BK also showed an inhibition on viral replication through the induction of IFN-alpha/beta expression. In conclusion, BK possessed antiviral activity against CVB1 infection. It interfered the early stage of viral replication and viral replication after infection through the induction of type I interferon expression.

Antiviral Agents↗

PubMed2006

Attenuated expression of interferon-induced protein kinase PKR in a simian cell devoid of type I interferons.

The interferon-induced, double-stranded RNA (dsRNA)-dependent protein kinase PKR plays a key role in interferon-mediated host defense against viral infection, and is implicated in cellular transformation and apoptosis. We have isolated a cDNA of simian PKR encoding a product with 83% amino acid identity to the human homolog and showed that PKR expression is significantly attenuated in the Vero E6 African green monkey kidney cells devoid of type I interferon genes. A variant form of PKR lacking the exon 12 in the kinase domain is produced in these cells, presumably from an alternatively spliced transcript. Unlike wild type PKR, the variant protein named PKR-DE12 is incapable of auto-phosphorylation and phosphorylation of eIF2-a, indicating that the kinase sub-domains III and IV embedded in exon 12 are indispensable for catalytic function. PKR-DE12 had no dominant negative effect but was weakly phosphorylated in trans by wild type PKR.

Adenoviruses, Simian↗

PubMed2006

Adrenergic inhibition of innate anti-viral response: PKA blockade of Type I interferon gene transcription mediates catecholamine support for HIV-1 replication.

Type I interferons (IFN-alpha and -beta) play a key role in anti-viral immunity, and we sought to define the molecular mechanisms by which the sympathetic nervous system (SNS) inhibits their effects. In peripheral blood leukocytes and plasmacytoid dendritic cells (pDC2), induction of interferon anti-viral activity by double-stranded RNA (poly-I:C) or CpG DNA was substantially inhibited by norepinephrine and by pharmacologic activation of the cAMP/PKA signaling pathway. This effect was specific to Type I interferons and driven by PKA-mediated repression of IFNA and IFNB gene transcription. Luciferase reporter analyses identified tandem interferon response factor-binding sites in positive regulatory domains I and III of the IFNB promoter as a key target of PKA inhibition. PKA suppression of Type I interferons was associated with impaired transcription of interferon response genes supporting the "anti-viral state", and was sufficient to account for norepinephrine-induced enhancement of HIV-1 replication. Given the ubiquitous role of Type I interferons in containing viral replication, PKA-mediated inhibition of IFN transcription could explain the stimulatory effects of catecholamines on a broad range of viral pathogens.

Autonomic Nervous System↗

PubMed2001

Participation of type I interferon in the decreased virulence of the UL13 gene-deleted mutant of herpes simplex virus type 1.

We isolated a UL13 gene-deleted mutant of the herpes simplex virus type 1 (HSV-1) strain VR3 (VRDelta13) and its revertant virus (VRDelta13R). This deletion mutant still had virus host shutoff (vhs) activity, although a previous report had suggested the possibility of a functional relation between the UL13 product, that is protein kinase (PK), and vhs activity. We compared the in vivo growth of these viruses in BALB/c mice. VRDelta13 was cleared in the early period of intraperitoneal infection. VRDelta13 had a higher sensitivity to the mouse type I interferon (IFN) and showed a higher level of IFN induction in the study period of infection than did VR3 and VRDelta13R. These results suggest that a nonspecific antiviral response (i.e., the IFN system) may contribute to this rapid inhibition of viral replication in vivo.

3T3 Cells↗

PubMed2005

The host type I interferon response to viral and bacterial infections.

Type I interferons (IFN) are well studied cytokines with anti-viral and immune-modulating functions. Type I IFNs are produced following viral infections, but until recently, the mechanisms of viral recognition leading to IFN production were largely unknown. Toll like receptors (TLRs) have emerged as key transducers of type I IFN during viral infections by recognizing various viral components. Furthermore, much progress has been made in defining the signaling pathways downstream of TLRs for type I IFN production. TLR7 and TLR9 have become apparent as universally important in inducing type I IFN during infection with most viruses, particularly by plasmacytoid dendritic cells. New intracellular viral pattern recognition receptors leading to type I IFN production have been identified. Many bacteria can also induce the up-regulation of these cytokines. Interestingly, recent studies have found a detrimental effect on host cells if type I IFN is produced during infection with the intracellular gram-positive bacterial pathogen, Listeria monocytogenes. This review will discuss the recent advances made in defining the signaling pathways leading to type I IFN production.

Animals↗

PubMed1996

The type-I interferon receptor. The long and short of it.

The type-I interferon receptor is a multisubunit receptor of the cytokine receptor superfamily. The production of specific monoclonal antibodies against the receptor and the cloning of different receptor subunits have contributed to understanding the type-I interferon receptor structure and function. The present article analyzes these new advances and the role of the different receptor subunits in type-I interferon signaling.

Binding Sites↗

PubMed1979

Type I interferon induced in mice by infection with Trypanosoma equiperdum.

Type II interferon is known to be produced in mice infected with Trypanosoma cruzi. Therefore, interferon production was investigated in mice infected with Trypanosoma equiperdum. Interferon was found in the sera of mice infected with T. equiperdum from day 1 after infection until death on day 5. The maximal level of interferon appeared before parasitemia was detected, a finding showing that the endogenous interferon probably had no significant influence on the course of infection. Unexpectedly, the serum interferon was characterized as type I by its stability at pH 2 and by its neutralization by antiserum to virus-induced mouse interferon. The production of two different types of interferon in mice infected with T. cruzi and T. equiperdum may have been due to the dissimilar life cycles of the two trypanosomes in the white mouse.

Animals↗

PubMed2005

Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity.

Suppressor of cytokine signaling 1 (SOCS1) is a critical regulator of cytokine signaling and immune responses. SOCS1-deficient mice develop severe inflammatory disease, but are very resistant to viral infections. Using neutralizing antibody to type I interferon (IFN-alpha and IFN-beta) and mice deficient in interferon-gamma or type I interferon receptor components (IFNAR1 or IFNAR2), we demonstrate here that SOCS1 deficiency amplified type I interferon antiviral and proinflammatory actions independently of interferon-gamma. The mechanism of the suppression of type I interferon responses by SOCS1 was distinct from that of other cytokines. SOCS1 associated with and regulated IFNAR1- but not IFNAR2-specific signals, abrogating tyrosine phosphorylation of transcription factor STAT1 and reducing the duration of antiviral gene expression. Thus, SOCS1 is an important in vivo inhibitor of type I interferon signaling and contributes to balancing its beneficial antiviral versus detrimental proinflammatory effects on innate immunity.

Animals↗

PubMed1996

Autocrine amplification of type I interferon gene expression mediated by interferon stimulated gene factor 3 (ISGF3).

Interferon regulatory factor (IRF)-1 and IRF-2 have been implicated for the virus-induced expression of the interferon-alpha and beta (type I IFN) genes. However, recent gene disruption studies in mice suggested the presence of other factor(s) interacting with overlapping promoter elements. In the present paper, we describe the characterization of a DNA binding factor which is strongly induced after virus infection and recognizes these promoter elements. After extensive purification, the factor was revealed to be identical to IFN-stimulated gene factor 3 (ISGF3), a transcription factor complex activated by IFN treatment. ISGF3 binds to the promoter element of IFN-beta, positive regulatory domain I (PRDI), with significantly higher affinity than IRF-1, 2, and mutational analysis of PRDI showed that the gene expression and binding of ISGF3, but not of IRF-1, 2, are highly correlated. Furthermore, our functional analysis involving a dominant negative inhibitor for ISGF3 activation and an anti-IFN neutralizing antibody clearly demonstrated the presence of a positive feedback path way for type I IFN genes mediated by ISGF3.

Animals↗

PubMed1988

Characterization of the human type I interferon receptor by ligand blotting.

The human type I interferon (IFN) receptor was characterized by ligand blotting. In this method, plasmalemma proteins or detergent-lysed whole-cell extracts from human Burkitt lymphoma cell lines were separated on polyacrylamide gels and subsequently transferred onto nitrocellulose sheets. Probing the blots with 3 x 10(-10) M 125I-labeled recombinant IFN-alpha A (125I-rIFN-alpha A) revealed an IFN-alpha-binding protein with an apparent molecular mass of 95 kDa (p95). Performing the electrophoretic run under reducing conditions completely abrogated the signal on the blot, indicating that the type I IFN receptor contains a disulfide bond essential for IFN binding. Optimal binding of 125I-rIFN-alpha A occurred at pH 9. The specificity of the binding reaction was established by simultaneously adding an excess of unlabeled IFN during incubation of the blots with 125I-rIFN-alpha A. The addition of either unlabeled IFN-alpha or IFN-beta, but not IFN-gamma, abolished the binding of 125I-rIFN-alpha A to p95. 125I-IFN-gamma at 1.25 x 10(-11) M bound to two proteins distinct from p95 with apparent molecular mass of 92 and 87 kDa, respectively. Saturability of 125I-rIFN-alpha A binding was demonstrated by probing a constant amount of membrane proteins with increasing amounts of 125I-rIFN-alpha A. Scatchard analysis of the binding data yielded an apparent Kd of 5.4 x 10(-10) M for the immobilized type I IFN receptor. The expression of p95 on IFN-alpha-resistant and -sensitive cells was indistinguishable. We conclude that p95 is the IFN-alpha/beta receptor and that two proteins (p92 and p87) can specifically bind IFN-gamma. These results indicate that ligand blotting is a versatile method for characterization of unmodified IFN receptors and IFN-receptor interaction and could also provide a new investigational approach for other cytokine receptor systems.

Blotting, Western↗

PubMed1995

Atypical porcine type I interferon. Biochemical and biological characterization of the recombinant protein expressed in insect cells.

A recombinant baculovirus was designed to express short porcine type I interferon (spI interferon), a novel and atypical type I interferon that was recently described as the product of a gene transcribed in pig trophoblast at the time of implantation in the uterus [Lefèvre, F. & Boulay, V.C. (1993) J. Biol. Chem. 268, 19,760-19,768]. The recombinant protein, secreted into the culture medium of Sf9 cells at 3 days post infection (60,000 IU/ml), was purified by ion-exchange and reverse-phase HPLC. N-terminal sequencing confirmed the predicted signal peptide cleavage site and therefore the size of the mature protein (149 amino acids), the shortest of all reported type I interferons. Purified spI interferon, with a specific antiviral activity using Madin-Darby bovine kidney cells of 3.7 x 10(7) IU/mg, is an N-glycosylated monomer of 19 kDa that possesses several physicochemical characteristics of interferons: (a) disulfide bonds are necessary for bioactivity; spI interferon is thermolabile, stable at pH 2, and able to renature after complete denaturation (1% 2-mercaptoethanol, 1% SDS, and 5 M urea); (b) the carbohydrate chain is not essential for bioactivity since no loss of antiviral activity is observed following complete deglycosylation. In this study, antiviral and anti-proliferation activities of spI interferon in cell culture were compared with those of other interferons, especially with porcine type 1 interferon-alpha. A major difference with porcine type 1 interferon-alpha was that spI interferon was not active on human cells in either test, and it was relatively more active on pig cells compared to bovine cells than porcine type 1 interferon-alpha. Serological cross-neutralization results obtained with anti-(spI interferon) serum confirmed that several members of interferon families are not antigenically related to spI interferon, in agreement with previous observations; this provides further evidence that spI interferon could represent a new family of type I interferon.

Amino Acid Sequence↗

PubMedDate not supplied

Viruses and the type I interferon antiviral system: induction and evasion.

The type I interferon (IFN) system responds to viral infection and induces an "antiviral state" in cells, providing an important first line of defense against virus infection. Interaction of type I IFNs (IFN alpha and IFN beta) with their receptor induces hundreds of cellular genes. Of the proteins induced by IFN, the antiviral function of only a few is known, and their mechanisms of action are only partly understood. Additionally, although viral-encoded mechanisms that counteract specific components of the type I IFN response have been known for some time, it has recently become clear that many (if not most) viruses encode some form of IFN-antagonist. Understanding the interplay between viral-encoded IFN antagonists and the interferon response will be essential if the therapeutic potential of IFNs is to be fully exploited.

Animals↗

PubMedDate not supplied

Mechanisms of type I interferon signaling in normal and malignant cells.

Type I interferons (IFNs) are cytokines that induce multiple biological effects on target cells, including antiviral, antiproliferative, and immunomodulatory activities. Consistent with the pleiotropic nature of these cytokines, multiple signaling pathways are activated during binding of IFNs to the type I IFN receptor. An important signaling cascade activated by type I IFNs is the Jak-Stat pathway. Activation of the Tyk-2 and Jak-1 kinases, and downstream formation of various Stat complexes, mediates IFN-dependent gene transcription for IFN-stimulated genes. In addition to the classic Jak-Stat pathway, type I IFNs activate multiple other pathways, including the insulin receptor substrate-phosphatidylinositol 3'-kinase cascade, the CBL-CrkL pathway, and mitogen-activated protein kinase pathways. There is accumulating evidence that non-Stat IFN-regulated signaling pathways play important roles in the generation of the antiproliferative effects of type I IFNs. In this review, the regulation of various signaling cascades by the type I IFN receptor is summarized and an update on recent advances in the field is provided.

Animals↗

PubMed2004

Mice lacking the type I interferon receptor are resistant to Listeria monocytogenes.

Listeria monocytogenes is a facultative intracellular pathogen that induces a cytosolic signaling cascade resulting in expression of interferon (IFN)-beta. Although type I IFNs are critical in viral defense, their role in immunity to bacterial pathogens is much less clear. In this study, we addressed the role of type I IFNs by examining the infection of L. monocytogenes in BALB/c mice lacking the type I IFN receptor (IFN-alpha/betaR-/-). During the first 24 h of infection in vivo, IFN-alpha/betaR-/- and wild-type mice were similar in terms of L. monocytogenes survival. In addition, the intracellular fate of L. monocytogenes in macrophages cultured from IFN-alpha/betaR-/- and wild-type mice was indistinguishable. However, by 72 h after inoculation in vivo, IFN-alpha/betaR-/- mice were approximately 1,000-fold more resistant to a high dose L. monocytogenes infection. Resistance was correlated with elevated levels of interleukin 12p70 in the blood and increased numbers of CD11b+ macrophages producing tumor necrosis factor alpha in the spleen of IFN-alpha/betaR-/- mice. The results of this study suggest that L. monocytogenes might be exploiting an innate antiviral response to promote its pathogenesis.

Animals↗