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At least 865 records · Page 48Linked to original sources
PubMed1988

Effect of interferon-alpha, interferon-gamma and tumour necrosis factor on African swine fever virus replication in porcine monocytes and macrophages.

Bovine interferon-alpha I1 (IFN-alpha I1) and porcine interferon-gamma (IFN-gamma) inhibited African swine fever virus replication in both porcine monocytes and alveolar macrophages. The most potent antiviral activity was observed with IFN-gamma-treated alveolar macrophages. The production of both a virulent (CC83) and a non-virulent (BA71) isolate of the virus was inhibited. Bovine tumour necrosis factor alpha did not show antiviral activity in either monocytes or alveolar macrophages. Rather, an increase of African swine fever virus production in tumour necrosis factor alpha-treated monocytes was found. An analysis of viral protein synthesis in IFN-alpha I1- and IFN-gamma-treated alveolar macrophages showed an inhibition of synthesis of some viral proteins. The inhibition of late proteins was very pronounced in IFN-gamma-treated cells, and it was probably a consequence of the inhibition of African swine fever virus DNA polymerase activity.

African Swine Fever Virus↗
PubMed2004

Inhibition of infectious human herpesvirus 8 production by gamma interferon and alpha interferon in BCBL-1 cells.

Human herpesvirus-8 (HHV-8) is aetiologically linked to Kaposi's sarcoma and primary effusion lymphoma. Although interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma) are both antiviral cytokines, IFN-alpha blocks entry of HHV-8 into the lytic phase, whereas IFN-gamma induces an increase in the percentage of cells undergoing lytic replication. Multiple events in the lytic cascade must be completed to produce infectious virus. The ability of both types of IFN to affect the production of infectious virus was explored. Both IFN-alpha and IFN-gamma induced expression of the antiviral proteins double-stranded RNA-activated protein kinase (PKR) and 2'5'-oligoadenylate synthetase (2'5'-OAS) in HHV-8-infected BCBL-1 cells. Higher levels resulted from incubation with IFN-alpha than with IFN-gamma, whereas IFN-gamma induced higher levels of IRF-1 than did IFN-alpha. IFN-gamma induced a minor increase in lytic viral gene expression, which was not accompanied by a detectable increase in infectious virus. When lytic replication of HHV-8 was induced using TPA, high levels of infectious virus appeared in the conditioned medium. When IFN-gamma was present during TPA stimulation, the production of infectious virus was reduced by at least a 60 %, and IFN-alpha fully blocked TPA-induced production of infectious virus. The greater reduction of viral production that occurred with IFN-alpha is consistent with the higher levels of the antiviral proteins PKR and 2'5'-OAS induced by IFN-alpha than by IFN-gamma. These studies indicate that the augmentation of cellular antiviral defences by IFN-gamma was sufficient to prevent production of infectious virus despite IFN-gamma-induced entry of some cells into the lytic phase of HHV-8 replication.

Cell Line↗
PubMedDate not supplied

The interferon-alpha 2b gene in Japanese patients with chronic viral hepatitis who developed antibodies after treatment with recombinant interferon-alpha 2a.

DNA was extracted from leucocytes of 23 Japanese patients with chronic viral hepatitis who received treatment with recombinant interferon-alpha 2a (IFN-alpha 2a) and nine healthy controls, as well as eight human cell lines of Caucasian or African origin. A part of the gene encoding IFN-alpha 2 was amplified by polymerase chain reaction and the sequence of nucleotides 1-231 was determined. Interferon-alpha 2a, -alpha 2b and -alpha 2c genes were tested for in five clones each from a patient or control, or a cell line, based on adenine or guanine at nucleotide positions 68 and 101. The IFN-alpha 2b gene was detected in all 160 clones from 23 Japanese patients and nine controls, but the IFN-alpha 2a or -alpha 2c gene was not found in any. Of five cell lines derived from Caucasians, four exhibited only the IFN-alpha 2b gene, while the remaining one exhibited both IFN-alpha 2a and -alpha 2b genes. Of three cell lines derived from Africans, one each showed only the IFN-alpha 2b or -alpha 2c gene, and the remaining one both IFN-alpha 2b and -alpha 2c genes. The 23 patients with the IFN-alpha 2b gene and chronic viral hepatitis included 10 who developed antibodies against IFN after treatment with recombinant IFN-alpha 2a. These results indicated a distinct geographical distribution of the three IFN-alpha 2 genes, and suggested the use of a recombinant IFN-alpha 2 preparation in agreement with the IFN-alpha 2 gene possessed by the recipient to avoid antibody responses.

Amino Acid Sequence↗
PubMed2006

Efficacy of interferon alpha-2b and lamivudine combination treatment in comparison to interferon alpha-2b alone in chronic delta hepatitis: a randomized trial.

BACKGROUND AND AIM: Delta hepatitis is characterized by rapidly progressive liver disease with adverse prognosis in most patients. Patients benefit from high doses and prolonged courses of interferon (IFN) therapy; however, lamivudine as a single agent has been disappointing. Data relating to the efficacy of IFN and lamivudine in combination is limited. The aim of this study was to test the efficacy of IFN-alpha 2b and lamivudine combination treatment in comparison to IFN-alpha 2b alone in patients with chronic delta hepatitis. METHODS: Twenty-six patients with chronic delta hepatitis were randomized into two groups. Twelve patients received IFN-alpha 2b alone (eight men, four women; mean +/- SD age: 43.83 +/- 8.57 years), and 14 patients received IFN-alpha 2b plus lamivudine combination (seven men, seven women; mean +/- SD age: 42.5 +/- 11.02 years). The dose of IFN-alpha 2b was 10 MU t.i.w. and of lamivudine was 100 mg/day. The groups were comparable in reference to serum alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin, albumin levels, histological activity and stage. Four patients (33.3%) in the IFN group and two (14.3%) in the combination group had cirrhosis (P = 0.2). The duration of treatment was 48 weeks with an untreated follow-up period of at least 96 weeks (mean +/- SD, 3.1 +/- 1.9 years). A liver biopsy was performed at the end of treatment. RESULTS: Eight patients from the IFN group and 11 from the combination group completed treatment. Serum ALT values became normal in 8/14 patients (57.1%) treated with IFN plus lamivudine and in 5/12 patients (41.7%) treated with IFN alone (P = 0.43). Serum hepatitis delta virus RNA was no longer detectable in nine of 14 (64.3%) patients treated with IFN plus lamivudine as compared to five of 12 (41.6%) patients treated with IFN alone (P = 0.024). In both groups female patients had significantly better virological response rate (P = 0.007). There was a significant improvement in histological activity in the combination group (mean decrease 5.27 +/- 1.08 score, P = 0.001), but not in the IFN group (mean decrease 1.44 +/- 1.59 score, P = 0.39). No significant improvement was observed in regards to fibrosis. Four of the 14 patients (28.6%) treated with combination therapy as compared to two of 12 patients treated with IFN (16.7%) were sustained virological responders (P = 0.47). The 5-year survival rate was 65% in the IFN group and 85% in the combination group (P > 0.05). CONCLUSION: Interferon and lamivudine in combination is an encouraging treatment method and may be superior to IFN alone in chronic delta hepatitis.

Adult↗
PubMed2006

Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-alpha therapy.

BACKGROUND: The efficacy of consensus interferon (CIFN), a synthetic IFN with optimised in vitro activity, was assessed in chronic hepatitis C virus (HCV) patients who had failed the pretreatment with interferon-alpha (IFNalpha) and ribavirin. METHODS: One hundred and three patients after non-response (n=69) or relapse (n=34) to IFNalpha+/-ribavirin were randomly assigned to high-dose induction (CIFN 27-->9 microg daily for 24 weeks, 9 microg t.i.w. for 24 weeks) or low-dose treatment (CIFN 18 microg t.i.w. for 12 weeks, 9 microg t.i.w. for 36 weeks); each with ribavirin 800 mg/day. Follow-up was 24 weeks. RESULTS: Non-responder patients treated with high-dose induction had higher early virological response rates (63% vs. 39%, P<0.05). This initial positive effect was lost during the last 24 weeks of treatment yielding sustained virological response (SVR) rates of 26% in both groups. Relapse patients revealed SVR in 70% and 38% in groups A and B (NS). Treatment was well tolerated with side effect-related preterm discontinuations in 8% and 5%. CONCLUSIONS: CIFN and ribavirin treatment induced considerable SVR rates in patients with non-response or relapse to IFNalpha+/-ribavirin. Viral elimination rates might be further increased by continuous daily administration of CIFN and weight-adjusted ribavirin dosing.

Adolescent↗
PubMed1998

Intravenous natural beta-interferon in white patients with chronic hepatitis C who are nonresponders to alpha-interferon.

OBJECTIVES: alpha-Interferons (alpha-IFN) have been shown to be effective in the treatment of chronic viral C hepatitis, but their efficacy remains unsatisfactory. Recently natural beta-interferon (beta-IFN) administered by intravenous infusion has been used successfully. METHODS: To evaluate the efficacy and safety of intravenous beta-IFN administration we treated 20 patients with histologically proven chronic hepatitis C who were nonresponders to at least two previous courses of alpha-IFN treatment. All patients received 6 million units (MU) of natural human fibroblast beta-IFN by drip infusion, 6 times per wk for 8 wk and were followed up for 6 months after suspension of treatment. RESULTS: Five patients (25%) had response at the end of treatment; of these patients only one had sustained response. Patients who responded to therapy had lower, although not significantly, baseline levels of HCV RNA, compared with nonresponders. Whereas mean viral load decreased during therapy, only two patients were HCV RNA negative at the end of treatment, but none were at the end of the follow-up period. Genotype 1 was found in 17 cases, genotype 2 was found in one case, and a combination of genotypes 1b and 2a was found in the remaining two cases. Therapy was well tolerated and beta-IFN administration was neither interrupted nor its dosage reduced due to side effects in any of the patients. CONCLUSIONS: Our study shows that intravenous beta-IFN is well tolerated and that the modest results obtained may depend on the brevity of treatment. Consequently, further studies are needed to define the optimum dose, schedule, and duration of treatment to eradicate HCV infection.

Adult↗
PubMed1972

Effect of interferon inducers and interferon on bacterial infections.

The effect of interferon inducers and exogenous L-cell interferon on the infection of mice by Pasteurella tularensis or Diplococcus pneumoniae was investigated. The results indicate that the degree of protection is dependent on the type of inducer used. A variety of defense mechanisms with limited nonspecific activity appear to be involved.

Animals↗
PubMed2007

Role of interferon regulatory factor 3 in type I interferon responses in rotavirus-infected dendritic cells and fibroblasts.

The main pathway for the induction of type I interferons (IFN) by viruses is through the recognition of viral RNA by cytosolic receptors and the subsequent activation of interferon regulatory factor 3 (IRF-3), which drives IFN-alpha/beta transcription. In addition to their role in inducing an antiviral state, type I IFN also play a role in modulating adaptive immune responses, in part via their effects on dendritic cells (DCs). Many viruses have evolved mechanisms to interfere with type I IFN induction, and one recently reported strategy for achieving this is by targeting IRF-3 for degradation, as shown for rotavirus nonstructural protein 1 (NSP1). It was therefore of interest to investigate whether rotavirus-exposed DCs would produce type I IFN and/or mature in response to the virus. Our results demonstrate that IRF-3 was rapidly degraded in rotavirus-infected mouse embryonic fibroblasts (MEFs) and type I IFN was not detected in these cultures. In contrast, rotavirus induced type I IFN production in myeloid DCs (mDCs), resulting in their activation. Type I IFN induction in response to rotavirus was reduced in mDCs from IRF-3(-/-) mice, indicating that IRF-3 was important for mediating the response. Exposure of mDCs to UV-treated rotavirus induced significantly higher type I IFN levels, suggesting that rotavirus-encoded functions also antagonized the response in DCs. However, in contrast to MEFs, this action was not sufficient to completely abrogate type I IFN induction, consistent with a role for DCs as sentinels for virus infection.

Animals↗
PubMed2006

In vitro treatment of human monocytes/macrophages with myristoylated recombinant Nef of human immunodeficiency virus type 1 leads to the activation of mitogen-activated protein kinases, IkappaB kinases, and interferon regulatory factor 3 and to the release of beta interferon.

The viral protein Nef is a virulence factor that plays multiple roles during the early and late phases of human immunodeficiency virus (HIV) replication. Nef regulates the cell surface expression of critical proteins (including down-regulation of CD4 and major histocompatibility complex class I), T-cell receptor signaling, and apoptosis, inducing proapoptotic effects in uninfected bystander cells and antiapoptotic effects in infected cells. It has been proposed that Nef intersects the CD40 ligand signaling pathway in macrophages, leading to modification in the pattern of secreted factors that appear able to recruit and activate T lymphocytes, rendering them susceptible to HIV infection. There is also increasing evidence that in vitro cell treatment with Nef induces signaling effects. Exogenous Nef treatment is able to induce apoptosis in uninfected T cells, maturation in dendritic cells, and suppression of CD40-dependent immunoglobulin class switching in B cells. Previously, we reported that Nef treatment of primary human monocyte-derived macrophages (MDMs) induces a cycloheximide-independent activation of NF-kappaB and the synthesis and secretion of a set of chemokines/cytokines that activate STAT1 and STAT3. Here, we show that Nef treatment is capable of hijacking cellular signaling pathways, inducing a very rapid regulatory response in MDMs that is characterized by the rapid and transient phosphorylation of the alpha and beta subunits of the IkappaB kinase complex and of JNK, ERK1/2, and p38 mitogen-activated protein kinase family members. In addition, we have observed the activation of interferon regulatory factor 3, leading to the synthesis of beta interferon mRNA and protein, which in turn induces STAT2 phosphorylation. All of these effects require Nef myristoylation.

Enzyme Activation↗
PubMed2007

Andes and Prospect Hill hantaviruses differ in early induction of interferon although both can downregulate interferon signaling.

Hantavirus pulmonary syndrome (HPS) is a severe respiratory disease which is thought to result from a dysregulated immune response to infection with pathogenic hantaviruses, such as Sin Nombre virus or Andes virus (ANDV). Other New World hantaviruses, such as Prospect Hill virus (PHV), have not been associated with human disease. Activation of an antiviral state and cell signaling in response to hantavirus infection were examined using human primary lung endothelial cells, the main target cell infected in HPS patients. PHV, but not ANDV, was found to induce a robust beta interferon (IFN-beta) response early after infection of primary lung endothelial cells. The level of IFN induction correlated with IFN regulatory factor 3 (IRF-3) activation, in that IRF-3 dimerization and nuclear translocation were detected in PHV but not ANDV infection. In addition, phosphorylated Stat-1/2 levels were significantly lower in the ANDV-infected cells relative to PHV. Presumably, this reflects the lower level of IRF-3 activation and initial IFN induced by ANDV relative to PHV. To determine whether, in addition, ANDV interference with IFN signaling also contributed to the low Stat-1/2 activation seen in ANDV infection, the levels of exogenous IFN-beta-induced Stat-1/2 activation detectable in uninfected versus ANDV- or PHV-infected Vero-E6 cells were examined. Surprisingly, both viruses were found to downregulate IFN-induced Stat-1/2 activation. Analysis of cells transiently expressing only ANDV or PHV glycoproteins implicated these proteins in this downregulation. In conclusion, while both viruses can interfere with IFN signaling, there is a major difference in the initial interferon induction via IRF-3 activation between ANDV and PHV in infected primary endothelial cells, and this correlates with the reported differences in pathogenicity of these viruses.

Animals↗
PubMed2006

"Self" and "nonself" manipulation of interferon defense during persistent infection: bovine viral diarrhea virus resists alpha/beta interferon without blocking antiviral activity against unrelated viruses replicating in its host cells.

Bovine viral diarrhea virus (BVDV), together with Classical swine fever virus (CSFV) and Border disease virus (BDV) of sheep, belongs to the genus Pestivirus of the Flaviviridae. BVDV is either cytopathic (cp) or noncytopathic (ncp), as defined by its effect on cultured cells. Infection of pregnant animals with the ncp biotype may lead to the birth of persistently infected calves that are immunotolerant to the infecting viral strain. In addition to evading the adaptive immune system, BVDV evades key mechanisms of innate immunity. Previously, we showed that ncp BVDV inhibits the induction of apoptosis and alpha/beta interferon (IFN-alpha/beta) synthesis by double-stranded RNA (dsRNA). Here, we report that (i) both ncp and cp BVDV block the induction by dsRNA of the Mx protein (which can also be induced in the absence of IFN signaling); (ii) neither biotype blocks the activity of IFN; and (iii) once infection is established, BVDV is largely resistant to the activity of IFN-alpha/beta but (iv) does not interfere with the establishment of an antiviral state induced by IFN-alpha/beta against unrelated viruses. The results of our study suggest that, in persistent infection, BVDV is able to evade a central element of innate immunity directed against itself without generally compromising its activity against unrelated viruses ("nonself") that may replicate in cells infected with ncp BVDV. This highly selective "self" and "nonself" model of evasion of the interferon defense system may be a key element in the success of persistent infection in addition to immunotolerance initiated by the early time point of fetal infection.

Animals↗
PubMed1989

Regulation of the interferon-inducible IFI-78K gene, the human equivalent of the murine Mx gene, by interferons, double-stranded RNA, certain cytokines, and viruses.

The interferon-inducible gene (IFI-78K gene) that codes for a human protein, p78, of 78,000 Mr is the equivalent of the mouse Mx gene encoding Mx protein. The IFI-78K gene is located on chromosome 21 together with the alpha/beta interferon (IFN-alpha/beta) receptor. The p78 protein is important since it may be involved in resistance to influenza viruses. The regulation of the IFI-78K gene was studied in human diploid cells by using a cDNA probe to p78 mRNA and specific monoclonal antibodies to p78 protein. The IFI-78K gene, a normally quiescent gene, is transcriptionally regulated by IFN-alpha, and its induction does not require protein synthesis. The rate of transcription measured in a run-on assay increased rapidly but transiently. The level of p78 mRNA increased up to 8 h, declining slowly afterwards. The p78 protein, undetectable in untreated cells, accumulated up to 16 h, and its amount remained stable for at least 36 h after the addition of IFN-alpha. Cytokines such as tumor necrosis factor, interleukin-1 alpha, and interleukin-1 beta activated the IFI-78K gene at concentrations comparable to that of IFN-alpha. However, gene activation by these cytokines required protein synthesis. Poly(rI)-poly(rC) induced the IFI-78K gene directly at the transcriptional level without requirement for protein synthesis. Newcastle disease virus, influenza virus, and to a lesser extent vesicular stomatitis virus also induced the IFI-78K gene in the absence of any protein synthesis. Induction of transcription by viruses was markedly enhanced by pretreatment of cells with IFN-gamma (which by itself is a poor inducer of the IFI-78K gene), resulting in accumulation of p78 protein during the course of infection; this suggests that IFN-gamma programs cells to full antiviral activity upon virus infection.

Blotting, Northern↗
PubMed1992

Mechanism of interferon action: alpha and gamma interferons differentially affect mRNA levels of the catalytic subunit of protein kinase A and protein Mx in human cells.

Treatment of human HeLa and amnion U cells with gamma interferon (IFN-gamma), either alone or in combination with alpha interferon (IFN-alpha), reduced the steady-state level of mRNA encoding the catalytic (C) subunit of protein kinase A (PKA) as measured by Northern gel-blot (RNA) analysis. In addition, IFN-gamma treatment increased the ratio of C alpha to C alpha 2 (the two splice-site variants of PKA C alpha subunit mRNA produced in HeLa cells) as measured by a polymerase chain reaction assay. IFN-gamma greatly reduced the amount of a novel splice-site variant of PKA, C alpha 2, which retains introns G and H, relative to the amount of C alpha, which lacks introns G and H. IFN-alpha treatment in combination with IFN-gamma did not further reduce the level of PKA C alpha transcripts beyond that of IFN-gamma alone, as measured by Northern blots; however, IFN-alpha in combination with IFN-gamma did cause a synergistic increase in the level of human Mx transcripts.

Base Sequence↗
PubMed1999

Interferon regulatory factor 3 is required for viral induction of beta interferon in primary cardiac myocyte cultures.

Viral myocarditis affects an estimated 5 to 20% of the human population. The antiviral cytokine beta interferon (IFN-beta) is critical for protection against viral myocarditis in mice. That is, nonmyocarditic reoviruses induce myocarditis in mice that lack IFN-alpha/beta, and nonmyocarditic reoviruses both induce more IFN-beta and are more sensitive to the antiviral effects of IFN-beta than myocarditic reoviruses in primary cardiac myocyte cultures. Induction of IFN-beta in certain cell types involves viral activation of the transcription factor interferon regulatory factor 3 (IRF-3). To address whether IRF-3 can induce IFN-beta in cardiac myocytes, primary cardiac myocyte cultures and control L929 cells were transfected with a plasmid constitutively expressing IRF-3. Overexpression of IRF-3 resulted in induction of IFN-beta in the absence of viral infection in both cell types. To address whether IRF-3 is required for viral induction of IFN-beta, cell cultures were transfected with a plasmid constitutively expressing a dominant negative IRF-3 protein. The dominant negative IRF-3 reduced reovirus induction of IFN-beta in control L929 cells and completely eliminated induction in primary cardiac myocyte cultures. This provides the first identification of a cardiac cellular factor required for viral induction of IFN-beta and the first report of any cell type requiring IRF-3 for this response.

Animals↗
PubMed2002

Inhibition of beta interferon transcription by noncytopathogenic bovine viral diarrhea virus is through an interferon regulatory factor 3-dependent mechanism.

The induction and inhibition of the interferon (IFN) response and apoptosis by bovine viral diarrhea virus (BVDV) has been examined. Here we show that prior infection of cells by noncytopathogenic BVDV (ncp BVDV) fails to block transcriptional responses to alpha/beta IFN. In contrast, ncp BVDV-infected cells fail to produce IFN-alpha/beta or MxA in response to double-stranded RNA (dsRNA) or infection with a heterologous virus (Semliki Forest virus [SFV]). ncp BVDV preinfection is unable to block cp BVDV- or SFV-induced apoptosis. The effects of ncp BVDV infection on the transcription factors controlling the IFN-beta induction pathway have been analyzed. The transcription factor NF-kappa B was not activated following ncp BVDV infection, but ncp BVDV infection was not able to block the activation of NF-kappa B by either SFV or tumor necrosis factor alpha. Furthermore, ncp BVDV infection did not result in the activation of stress kinases (JNK1 and JNK2) or the phosphorylation of transcription factors ATF-2 and c-Jun; again, ncp BVDV infection was not able to block their activation by SFV. Interferon regulatory factor 3 (IRF-3) was shown to be translocated to the nuclei of infected cells in response to ncp BVDV, although DNA-binding of IRF-3 was not seen in nuclear extracts. In contrast, an IRF-3-DNA complex was observed in nuclear extracts from cells infected with SFV, but the appearance of this complex was blocked when cells were previously exposed to ncp BVDV. We conclude that the inhibition of IFN induction by this pestivirus involves a block to IRF-3 function, and we speculate that this may be a key characteristic for the survival of pestiviruses in nature.

Animals↗
PubMed2005

Inhibition of Beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3.

Severe acute respiratory syndrome (SARS) is caused by a novel coronavirus termed SARS-CoV. We and others have previously shown that the replication of SARS-CoV can be suppressed by exogenously added interferon (IFN), a cytokine which is normally synthesized by cells as a reaction to virus infection. Here, we demonstrate that SARS-CoV escapes IFN-mediated growth inhibition by preventing the induction of IFN-beta. In SARS-CoV-infected cells, no endogenous IFN-beta transcripts and no IFN-beta promoter activity were detected. Nevertheless, the transcription factor interferon regulatory factor 3 (IRF-3), which is essential for IFN-beta promoter activity, was transported from the cytoplasm to the nucleus early after infection with SARS-CoV. However, at a later time point in infection, IRF-3 was again localized in the cytoplasm. By contrast, IRF-3 remained in the nucleus of cells infected with the IFN-inducing control virus Bunyamwera delNSs. Other signs of IRF-3 activation such as hyperphosphorylation, homodimer formation, and recruitment of the coactivator CREB-binding protein (CBP) were found late after infection with the control virus but not with SARS-CoV. Our data suggest that nuclear transport of IRF-3 is an immediate-early reaction to virus infection and may precede its hyperphosphorylation, homodimer formation, and binding to CBP. In order to escape activation of the IFN system, SARS-CoV appears to block a step after the early nuclear transport of IRF-3.

Animals↗
PubMed2005

Analysis of genes induced by Sendai virus infection of mutant cell lines reveals essential roles of interferon regulatory factor 3, NF-kappaB, and interferon but not toll-like receptor 3.

Sendai virus (SeV) infection causes the transcriptional induction of many cellular genes that are also induced by interferon (IFN) or double-stranded RNA (dsRNA). We took advantage of various mutant cell lines to investigate the putative roles of the components of the IFN and dsRNA signaling pathways in the induction of those genes by SeV. Profiling the patterns of gene expression in SeV-infected cells demonstrated that Toll-like receptor 3, although essential for gene induction by dsRNA, was dispensable for gene induction by SeV. In contrast, Jak1, which mediates IFN signaling, was required for the induction of a small subset of genes by SeV. NF-kappaB and interferon regulatory factor 3 (IRF-3), the two major transcription factors activated by virus infection, were essential for the induction of two sets of genes by SeV. As expected, some of the IRF-3-dependent genes, such as ISG56, were more strongly induced by SeV in IRF-3-overexpressing cells. Surprisingly, in those cells, a number of NF-kappaB-dependent genes, such as the A20 gene, were induced poorly. Using a series of cell lines expressing increasing levels of IRF-3, we demonstrated that the degree of induction of A20 mRNA, upon SeV infection, was inversely proportional to the cellular level of IRF-3, whereas that of ISG56 mRNA was directly proportional. Thus, IRF-3 can suppress the expression of NF-kappaB-dependent genes in SeV-infected cells.

Cell Line↗