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Results for “Interferon signalling”

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At least 37 records · Page 2Linked to original sources
PubMed2006

Retinoic acid-induced protein ISGylation is dependent on interferon signal transduction.

Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like modifier that forms conjugates with target protein substrates. As its name suggests, its expression and conjugation to other proteins are highly regulated by interferon (IFN). It was recently demonstrated that ISG15 expression, ISG15 conjugation, and several enzymes involved in ISG15 modification are upregulated in an acute promyelocytic cell line following treatment with retinoic acid, suggesting a possible retinoic acid induced IFN-independent ISG15 modification pathway. In this study, we examined a possible link between IFN signaling and retinoic acid-induced ISG15 conjugation. We observed that ISGylation can be induced by retinoic acid in two myeloid leukemia cell lines. By sandwich ELISA, we detected increased IFN secretion into cell culture media following retinoic acid treatment. Blockade of the type I IFN receptor with a neutralizing antibody blocked retinoic acid induced ISG15 expression and ISG15 conjugation. Taken together, these data suggested that retinoic acid-induced secretion of IFN plays a fundamental role in retinoic acid promoted ISGylation.

Antineoplastic Agents↗
PubMed2003

Role of Stat5 in type I interferon-signaling and transcriptional regulation.

Type I interferons are pleiotropic cytokines that transduce signals via activation of multiple downstream signaling cascades, including the Jak-Stat pathway. Although the roles of Stat1 and Stat2 in Type I interferon signaling are well established, the roles that other Stat-family members play in the induction of IFN-responses remain to be defined. In previous studies, we have shown that Stat5 associates with the CrkL adapter and forms a signaling complex that binds DNA. In the present study, we provide evidence that Stat5 is phosphorylated on serines 725/730 in an IFNalpha- and IFNbeta-dependent manner, providing direct evidence that serine phosphorylation of the protein is a component of an interferon signaling cascade. Such serine phosphorylation of Stat5 is Map kinase- and PI 3(')-kinase independent, while the activation of the serine kinase that phosphorylates Stat5 is regulated by upstream tyrosine kinase activity. Using mouse embryonic fibroblasts with targeted disruption of the Stat5a and Stat5b genes, we demonstrate that full activation of Stat5 is required for Type I interferon-dependent gene transcription via GAS elements. Altogether, our data provide evidence that Stat5 plays an important role in IFN-signaling and participates in the induction of Type I IFN-dependent responses. Furthermore, our results strongly suggest that, in addition to phosphorylation on tyrosine residues, phosphorylation on serine residues exhibits regulatory effects on the transcriptional capacity of Stat5.

Animals↗
PubMed2006

Inhibition of interferon signaling by the Kaposi's sarcoma-associated herpesvirus full-length viral interferon regulatory factor 2 protein.

Interferon (IFN) signal transduction involves interferon regulatory factors (IRF). Kaposi's sarcoma-associated herpesvirus (KSHV) encodes four IRF homologues: viral IRF 1 (vIRF-1) to vIRF-4. Previous functional studies revealed that the first exon of vIRF-2 inhibited alpha/beta interferon (IFN-alpha/beta) signaling. We now show that full-length vIRF-2 protein, translated from two spliced exons, inhibited both IFN-alpha- and IFN-lambda-driven transactivation of a reporter promoter containing the interferon stimulated response element (ISRE). Transactivation of the ISRE promoter by IRF-1 was negatively regulated by vIRF-2 protein as well. Transactivation of a full-length IFN-beta reporter promoter by either IRF-3 or IRF-1, but not IRF-7, was also inhibited by vIRF-2 protein. Thus, vIRF-2 protein is an interferon induction antagonist that acts pleiotropically, presumably facilitating KSHV infection and dissemination in vivo.

Cell Line↗
PubMed2002

Type I-interferon signalling in fish.

Type I interferon (IFN) signalling uses a dual mechanism of action. A Jak-Stat pathway extensively described in mammals involves a cascade of reactions from the interaction of the IFN molecule with its membrane receptor to the stimulation of IFN-induced gene promoters leading in turn to an antiviral state. Regulation of IFN activity is also mediated by two DNA-binding transcription factors called interferon regulatory factor (IRF)-1 and -2, that respectively stimulate and repress the promoter of IFN-induced genes. By gene walking with trout genomic DNA the regulatory sequence of the IRF-1 gene was cloned and sequenced. Sequence analysis showed that this 1 Kb 5' flanking region has a structure which is typical for an IFN-induced gene promoter. It contains a TATA box between -28 to -31, and a NF kappa B site between -41 and -52. No complete interferon stimulatory response element (ISRE) could be found, but ten GAAA motifs, which are characteristic of IFN-induced gene promoters, were found. In rainbow trout gonad (RTG) cells, IRF-1 is expressed constitutively and up-regulated by poly I:C but not by LPS. Transient transfections of RTG cells with a reporter construct based on the luciferase gene show that the IRF1 5' flanking region described above, is sufficient to allow the expression of luciferase and is capable of induction by dsRNA (poly I:C).

Animals↗
PubMed2002

Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of alpha/beta interferon signal transduction.

The alpha/beta interferon (IFN-alpha/beta)-induced STAT signal transduction pathway leading to activation of the ISGF3 transcription complex and subsequent antiviral responses is the target of viral pathogenesis strategies. Members of the Rubulavirus genus of the Paramyxovirus family of RNA viruses have acquired the ability to specifically target either STAT1 or STAT2 for proteolytic degradation as a countermeasure for evading IFN responses. While type II human parainfluenza virus induces STAT2 degradation, simian virus 5 induces STAT1 degradation. The components of the IFN signaling system that are required for STAT protein degradation by these paramyxoviruses have been investigated in a series of human somatic cell lines deficient in IFN signaling proteins. Results indicate that neither the IFN-alpha/beta receptor, the tyrosine kinases Jak1 or Tyk2, nor the ISGF3 DNA-binding subunit, IFN regulatory factor 9 (IRF9), is required for STAT protein degradation induced by either virus. Nonetheless, both STAT1 and STAT2 are strictly required in the host cell to establish a degradation-permissive environment enabling both viruses to target their respective STAT protein. Complementation studies reveal that STAT protein-activating tyrosine phosphorylation and functional src homology 2 (SH2) domains are dispensable for creating a permissive STAT degradation environment in degradation-incompetent cells, but the N terminus of the missing STAT protein is essential. Protein-protein interaction analysis indicates that V and STAT proteins interact physically in vitro and in vivo. These results constitute genetic and biochemical evidence supporting a virus-induced, IFN-independent STAT protein degradation complex that contains at least STAT1 and STAT2.

Animals↗
PubMed2005

Mitogen-activated protein kinase pathways in interferon signaling.

There is recent evidence that in addition to the classic JAK/STAT pathways, mitogen-activated proteins (MAP) kinase pathways play important roles in Type I interferon signaling and the generation of interferon responses. In particular, the p38 MAP kinase cascade exerts positive regulatory roles on transciptional activation of interferon-sensitive genes (ISGs) and the induction of the antiproliferative and antiviral properties of interferons. In this chapter, methodologies to detect activation of p38 and various upstream and downstream effectors are provided. Also, the methodological approaches used to examine the role of this pathway on the regulation of hematopoiesis are discussed.

Animals↗
PubMed2006

Defining the transcriptome of accelerated and replicatively senescent keratinocytes reveals links to differentiation, interferon signaling, and Notch related pathways.

Epidermal keratinocytes (KCs) undergo highly orchestrated morphological and molecular changes during transition from proliferative compartment into growth arrested early and late differentiation layers, prior to dying in outermost cornified layers of normal skin. Creation of stratum corneum is vital to barrier function protecting against infection. Transcriptional events in KCs regulating complex processes of differentiation and host defense required to maintain constant epidermal thickness and resistance to infection in either young or aged skin are largely unknown. Furthermore, as terminal differentiation is characterized by irreversible loss of replicative potential culminating in dead layers at the skin surface, this process may be viewed as a form of senescence. However, a complete transcriptional profile of senescent (SN) human KCs has not been previously defined to permit delineation of molecular boundaries involving differentiation and senescence. To fill this void, we utilized global transcriptional analysis of KCs maintained in vitro as either cultures of proliferating (PR) cells, early and late confluent (LC) (accelerated senescence) cultures, or KCs undergoing replicative senescence. Global gene expression profiling revealed early confluent (EC) KCs were somewhat similar to PR KCs, while prominent differences were evident when compared to LC KCs; which were also distinct from replicatively SN KCs. While confluent KCs have in common several genes regulating differentiation with replicatively SN KCs, the latter cells expressed elevated levels of genes involved in interferon signaling and inflammatory pathways. These results provide new insights into cell autonomous transcriptional-based programs operative within KCs contributing to replicative senescence, with partial sharing of genes involved in differentiation. In addition, regulation of KC senescence may involve participation of interferon signaling pathways derived from the important role of KCs in protecting skin from infection. Integrating all of the transcriptional data revealed a key role for Notch receptor mediated signaling in the confluency induced differentiation phenotype using this model system.

Apoptosis↗
PubMed2003

Convergence of the NF-kappaB and interferon signaling pathways in the regulation of antiviral defense and apoptosis.

The ubiquitously expressed interferon regulatory factor 3 (IRF-3) is directly activated following virus infection and functions as a key activator of the immediate-early Type 1 interferon (IFN) genes. Using DNA microarray analysis (8,556 genes) in Jurkat T cells inducibly expressing constitutively active IRF-3, several target genes directly regulated by IRF-3 were identified. Among the genes upregulated by IRF-3 were transcripts for a subset of known IFN-stimulated genes (ISGs), including ISG56, which functions as an inhibitor of translation initiation. Phosphorylation of C-terminal Ser/Thr residues--(382)GGASSLENTVDLHISNSHPLSLTSDQY(408)-is required for IRF-3 activation. Using C-terminal point mutations and a novel phosphospecific antibody, Ser396 was characterized as the minimal phosphoacceptor site required in vivo for IRF-3 activation following Sendai virus (SeV) infection, expression of viral nucleocapsid, or double-stranded RNA (dsRNA) treatment. The identity of the virus-activated kinase (VAK) activity that targets and activates IRF-3 and IRF-7 has remained a critical missing link in the understanding of interferon signaling. We report that the IKK-related kinases-IKKepsilon/TBK-1-are components of VAK that mediate IRF-3 and IRF-7 phosphorylation and thus functionally link the NF-kappaB and IRF pathways in the development of the antiviral response.

Amino Acid Sequence↗
PubMed2005

Regulation of the transcriptional activity of the IRF7 promoter by a pathway independent of interferon signaling.

Genes containing an interferon (IFN)-stimulated response element (ISRE) can be divided into two groups according to their inducibility by IFN and virus infection: one induced only by IFN and the other induced by both IFN and virus infection. Although it is now clear that IFN regulatory factor 7 (IRF7) is a multifunctional gene essential for induction of type I IFNs, regulation of the IRF7 promoter (IRF7p) is poorly understood. The IRF7 gene includes two IFN responsive elements, an IRF-binding element (IRFE) in the promoter region and an ISRE in the first intron, and is induced by the IFN-triggered Jak-STAT pathway by binding of the IFN-stimulated gene factor 3 (ISGF3) complex to the ISRE. In this study, we demonstrate that IRF3 and IRF7, which with the coactivators CREB-binding protein and P300 form the virus-activated factor (VAF) complex upon Sendai virus infection, bind to the IRF7 ISRE and IRFE and can directly activate IRF7 transcription. Promoter reporter assays show that both the ISRE and IRFE are responsive to activation by IRF7 and IRF3. In cells transiently expressing IRF7 or/and IRF3, the VAF level and binding of VAF are clearly increased after Sendai virus infection. Studies with Jak1 kinase inactive 293 cells that were stably transfected with a Jak1 kinase dead dominant negative construct, and the mutant cell lines SAN (IFNalpha-/beta-), U2A (IRF9-), U4A (Jak1-), and DKO (IRF1-/IRF2-) show that the IRF7 transcription activated directly by VAF is distinct from and independent of the IFN signaling pathway. Thus, IRF7 transcription is autoregulated by binding of the IRF7-containing VAF to its own ISRE and IRFE. The results show two distinct mechanisms for the activation of the IRF7 promoter, by IFN and by virus infection. A regulatory network between type I IFNs and IRF7 is proposed. The distinct pathways may reflect special roles for an efficient antiviral response at different stages of virus infection.

Cell Line↗
PubMed2006

Interferon signalling network in innate defence.

Interferons (IFNs) elicit multifaceted effects in host innate defence. Accumulating evidence revealed that not only the first identified Jak-Stat pathway but also other newly found signalling pathways are required for the induction of versatile responses by IFNs. In particular, type I IFNs are inducible by viral infection through the recognition of pathogen-associated molecules by pattern recognition receptors, and the induction of multiple IFN-stimulated genes through the activation of type I IFN signalling confers antiviral and immunomodulatory activities. Any step in this process is often targeted by viruses for their immuno-evasion. The regulatory function of constitutive IFN-alpha/beta signalling has been recognized in terms of its boosting effect on cellular responsiveness in host defence systems. Further comprehensive understanding of IFN signalling may offer a better direction to unravelling the complex signalling networks in the host defence system, and may contribute to their more effective therapeutic applications.

Animals↗
PubMed2001

Molecular cross-talk between the TRAIL and interferon signaling pathways.

TRAIL/APO-2L induces apoptosis in a variety of transformed cells and has potential as an anti-cancer therapeutic. The physiologic role of TRAIL is presumably more complex than merely activating caspase-mediated cell death. To shed light into TRAIL-mediated signaling, we used DNA microarrays to profile gene expression mediated by TRAIL in breast carcinoma cells. Primary response genes induced by TRAIL included a number of known NF-kappaB-dependent genes such as cIAP2, A20, and E-selectin. Remarkably, global transcriptome analysis revealed that TRAIL also induced a cohort of genes related to the interferon-signaling pathway. Assessing interferon-induced gene expression suggested various points of interaction with the TRAIL signaling pathway. Interestingly, while we observed interferon-mediated up-regulation of TRAIL, we also demonstrated a concomitant TRAIL-mediated induction of interferon-beta. Combining TRAIL and interferon in vitro, synergistically induced apoptosis and caspase activation in breast cancer cells. Together, these data indicate multiple levels of molecular cross-talk between the two diverse cytokines with anti-tumor properties.

Apoptosis↗
PubMed2004

Induction of suppressor of cytokine signaling-3 by herpes simplex virus type 1 contributes to inhibition of the interferon signaling pathway.

We showed previously that herpes simplex virus type 1 (HSV-1) suppresses the interferon (IFN) signaling pathway during the early infection stage in the human amnion cell line FL. HSV-1 inhibits the IFN-induced phosphorylation of Janus kinases (JAK) in infected FL cells. In the present study, we showed that the suppressor of cytokine signaling-3 (SOCS3), a host negative regulator of the JAK/STAT pathway, is rapidly induced in FL cells after HSV-1 infection. Maximal levels of SOCS3 protein were detected at around 1 to 2 h after infection. This is consistent with the occurrence of HSV-1-mediated inhibition of IFN-induced JAK phosphorylation. The HSV-1 wild-type strain VR3 induced SOCS3 more efficiently than did mutants that are defective in UL41 or UL13 and that are hyperresponsive to IFN. Induction of the IRF-7 protein and transcriptional activation of IFN-alpha4, which occur in a JAK/STAT pathway-dependent manner, were poorly induced by VR3 but efficiently induced by the mutant viruses. In contrast, phosphorylation of IRF-3 and transcriptional activation of IFN-beta, which are JAK/STAT pathway-independent process, were equally well induced by the wild-type strain and the mutants. In conclusion, the SOCS3 protein appears to be mainly responsible for the suppression of IFN signaling and IFN production that occurs during HSV-1 infection.

Cell Line↗
PubMed2002

Human cytomegalovirus inhibition of major histocompatibility complex transcription and interferon signal transduction.

Pathogens have evolved diverse mechanisms for escaping host innate and adaptive immunity. Viruses that maintain a persistent infection are particularly effective at disabling key arms of the host immune response. For example, the herpesviruses establish a persistent infection in human and animal hosts, in part through critical immunoevasive strategies. Cytomegalovirus, a beta-herpesvirus, impairs major histocompatibility complex (MHC) class I and class II antigen presentation by decreasing MHC expression on the surface of the infected cell, thus enabling infected cells to escape CD8+ and CD4+ T lymphocyte immunosurveillance. Moreover, cytomegalovirus blocks the interferon signal transduction pathway, thereby limiting the direct and indirect antiviral effects of the interferons. In this review, we focus on an emerging paradigm in which the effectiveness of viruses, particularly human cytomegalovirus, to escape antiviral immune responses is significantly enhanced by their ability to inhibit MHC transcription and interferon (IFN)-stimulated (JAK/STAT) signal transduction.

Antigen Presentation↗
PubMed2006

The Epstein-Barr virus-encoded LMP-1 oncoprotein negatively affects Tyk2 phosphorylation and interferon signaling in human B cells.

Epstein-Barr virus (EBV) establishes a persistent infection in the human host and is associated with a variety of human cancers. Persistent infection results from a balance between the host immune response and viral immune evasion mechanisms. EBV infection is controlled initially by the innate immune response and later by T-cell-mediated adaptive immunity. EBV has evolved mechanisms to evade the host immune response so that it can persist for the lifetime of the host. Latent membrane protein 1 (LMP-1) is the EBV oncoprotein essential for B-cell immortalization by EBV. We show here that LMP-1 interacts with Tyk2, a signaling intermediate in the alpha interferon (IFN-alpha) signaling pathway, via a previously uncharacterized LMP-1 signaling domain. LMP-1 prevents Tyk2 phosphorylation and inhibits IFN-alpha-stimulated STAT2 nuclear translocation and interferon-stimulated response element transcriptional activity. Long-term culture of EBV+ lymphoblastoid cells in IFN-alpha is associated with outgrowth of a population expressing elevated LMP-1 protein levels, suggesting that cells expressing higher levels of LMP-1 survive the antiproliferative selective pressure imposed by IFN-alpha. These results show that LMP-1 can protect EBV+ cells from the IFN-alpha-stimulated antiviral/antiproliferative response and suggest that chronic IFN-alpha treatment may encourage the outgrowth of cells expressing elevated, and therefore potentially oncogenic, LMP-1 levels in EBV+ individuals.

B-Lymphocytes↗
PubMed1997

KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus linked to the development of Kaposi's sarcoma and a rare B cell lymphoma, primary effusion lymphoma. The KSHV gene ORF K9 encodes vIRF which is a protein with low but significant homology to members of the interferon (IFN) regulatory factor (IRF) family responsible for regulating intracellular interferon signal transduction (Moore PS, Boshoff C, Weiss RA and Chang Y. (1996). Science, 274, 1739-1744). vIRF inhibits IFN-beta signal transduction as measured using an IFN-responsive ISG54 reporter construct co-transfected with ORF K9 into HeLa and 293 cells. vIRF also suppresses genes under IFN regulatory control as shown by inhibition of the IFN-beta inducibility of p21WAF1/CIP1, however, no direct DNA-binding or protein-protein interactions characteristic for IRF repressor proteins were identified. Stable transfectant NIH3T3 clones expressing vIRF grew in soft agar and at low serum concentrations, lost contact inhibition and formed tumors after injection into nude mice indicating that vIRF has the properties of a viral oncogene. Since vIRF is primarily expressed in KSHV-infected B cells, not KS spindle cells, this study suggests that vIRF is a transforming oncogene active in B cell neoplasias that may provide a unique immune escape mechanism for infected cells. This data is consistent with tumor suppressor pathways serving a dual function as host cell antiviral pathways.

3T3 Cells↗
PubMed1991

Do second messengers play a role in interferon signal transduction?

The signalling pathway by which the binding of interferons (IFNs, alpha and beta) to their receptor elicits its biological activity, the activation of the transcription of a distinct set of genes called the IFN-stimulated genes (ISG), is far from clear. Debate continues about whether interferon-receptor interaction results directly in gene activation or if second messengers are involved. In this article, we will discuss the evidence that rapid and transient changes in lipid metabolism and the activation of specific isoforms of protein kinase C (PKC) are involved in the initial signalling of interferon activation.

Animals↗
PubMed1999

Viral inhibition of interferon signal transduction.

The type I and II interferons (IFNs) are potent stimulators of antigen processing and presentation and are essential in antiviral immunity. IFNs upregulate the transcription of major histocompatibility complex (MHC) class I and II molecules, associated antigen-processing proteins, and induce the production of direct antiviral effector molecules such as 2',5'-oligoadenylate synthetase, double-stranded-RNA-dependent protein kinase and Mx proteins. It is increasingly evident that viruses have evolved mechanisms to globally inhibit the actions of IFNs through disruption of their signal transduction pathways. Herein, we review the ability and novel mechanisms of several diverse viruses to inhibit IFN-induced JAK/STAT signal transduction.

Humans↗
PubMed2005

The role of ICP0-Null HSV-1 and interferon signaling defects in the effective treatment of breast adenocarcinoma.

Oncolytic viruses that selectively replicate in cancer cells have been described for over 50 years. Despite the observation by several groups that multimutated herpes simplex type 1 vectors are oncolytic in a variety of murine tumor models, the oncolytic potential of ICP0 null mutants has not been described. This study characterizes a novel second-generation oncolytic herpes simplex type 1 vector null for the ICP0 gene. We tested three mutant viruses and found that all were selectively cytotoxic in a variety of human and murine tumor cells in vitro. Furthermore, we provide evidence of a mechanistic link between ICP0's function in interferon signaling pathways and the observed oncolytic capacity of ICP0 mutants. Using an immunocompetent murine model of breast adenocarcinoma we demonstrate that the ICP0 mutant KM100 completely eradicates tumors in approximately 80% of treated animals and significantly increases survival. Our data suggest that active viral replication is necessary for effective tumor regression. In addition, we characterized the potential of KM100 as an anti-tumor vaccine since cured mice were found to elicit a robust anti-tumor immune response and were refractory to subsequent tumor growth upon rechallenge.

Adenocarcinoma↗