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PubMed2001

Expression of nuclear transcription factor interferon consensus sequence binding protein in chronic myeloid leukemia correlates with pretreatment risk features and cytogenetic response to interferon-alpha.

Recently, it was shown that interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor (IRF) family, has a potential role in chronic myeloid leukemia (CML). Deletion of ICSBP gene in mice leads to a CML-like syndrome and samples from CML patients exhibited impaired ICSBP expression. The present study found that ICSBP expression correlated with risk features determined by Sokal score in untreated CML (P =.007 for high versus low risk). In addition, analyzing ICSBP expression during interferon-alpha (IFN-alpha) therapy in "good" (n = 27) versus "poor" (n = 15) cytogenetic responders, high ICSBP levels were only observed in "good" responders (P =.0002). Together, these data suggest that ICSBP levels are related to initial presentation of CML and the therapeutic response of CML to IFN-alpha, indicating an important role of ICSBP in CML. (Blood. 2001;97:3648-3650)

Cytogenetic Analysis↗
PubMed2000

Expression of interferon regulatory factor 4 in chronic myeloid leukemia: correlation with response to interferon alfa therapy.

PURPOSE: Mice experiments have established an important role for interferon regulatory factor (IRF) family members in hematopoiesis. We wanted to study the expression of interferon regulatory factor 4 (IRF4) in various hematologic disorders, especially chronic myeloid leukemia (CML), and its association with response to interferon alfa (IFN-alpha) treatment in CML. MATERIALS AND METHODS: Blood samples from various hematopoietic cell lines, different leukemia patients (70 CML, 29 acute myeloid leukemia [AML], 10 chronic myelomonocytic leukemia [CMMoL], 10 acute lymphoblastic leukemia, and 10 chronic lymphoid leukemia patients), and 33 healthy volunteers were monitored for IRF4 expression by reverse transcriptase polymerase chain reaction. Then, with a focus on CML, the IRF4 level was determined in sorted cell subpopulations from CML patients and healthy volunteers and in in vitro-stimulated CML cells. Furthermore, IRF4 expression was compared in the CML samples taken before IFN-alpha therapy and in 47 additional CML samples taken during IFN-alpha therapy. IRF4 expression was then correlated with cytogenetic response to IFN-alpha. RESULTS: IRF4 expression was significantly impaired in CML, AML, and CMMoL samples. The downregulation of IRF4 in CML samples was predominantly found in T cells. In CML patients during IFN-alpha therapy, a significant increase in IRF4 levels was detected, and this was also observed in sorted T cells from CML patients. The increase seen during IFN-alpha therapy was not due to different blood counts. In regard to the cytogenetic response with IFN-alpha, a good response was associated with high IRF4 expression. CONCLUSION: IRF4 expression is downregulated in T cells of CML patients, and its increase is associated with a good response to IFN-alpha therapy. These data suggest IRF4 expression as a useful marker to monitor, if not predict, response to IFN-alpha in CML.

Acute Disease↗
PubMed2001

Treatment of chronic hepatitis C patients with combination of alpha-interferon and ribavirin, consensus and pegylated interferons.

Hepatitis C is a major health problem. In recent years, the treatment of choice is alpha-interferon in combination with ribavirin. For patients with failure of this treatment the therapy with consensus or pegylated interferons, in monotherapy or in combination with ribavirin, present other possibilities. We can expect the development more potent antiviral drugs or immune modulators for patients, which are primary resistant to alpha-interferon. (Tab. 3, Ref. 31)

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↗
PubMed1994

Synthetic mimics of juxtaposed amino- and carboxyl-terminal peptide domains of human gamma interferon block ligand binding to human gamma interferon receptor.

The epitopes of two neutralizing antibodies (47N3-6 and 47N30A35) raised against rhuIFN-gamma each mapped both to amino-terminal regions (22-29 and 12-19, respectively) and to a carboxyl-terminal region 131-139, suggesting the juxtaposition of these two domains in the native protein. Three novel peptides were designed to mimic a conformation of rhuIFN-gamma that places the two regions in close proximity (discontinuous peptides 1 (15-21-GGG-132-138), 2 (15-29...111-118...130-138), and 3 (15-21-CGPGC-130-138)), by bridging the amino- and carboxyl-terminal regions of gamma interferon. Each discontinuous peptide inhibits biological or receptor binding activities with an IC50 of 15-50 microM and produces a neutralizing antibody when used as an immunogen. Neutralizing rabbit polyclonal antibody (P616) raised against discontinuous peptide 1 was used as immunogen to generate an anti-idiotypic response. This anti-idiotypic antibody inhibits receptor binding and recognizes soluble gamma interferon receptor on direct enzyme-linked immunosorbent assay. The anti-idiotypic response suggests that juxtaposed regions at the amino and carboxyl termini serve as the receptor-ligand binding site of human gamma interferon.

Amino Acid Sequence↗
PubMed2004

The significance of interferon and ribavirin combination therapy followed by interferon monotherapy for patients with chronic hepatitis C in Japan.

One hundred seventy-one patients with chronic hepatitis C were included in this study (genotype1 and high viral loads (1H), [Formula: see text]; non-1H, [Formula: see text]; N.D., [Formula: see text] ). The combination therapy of interferon and ribavirin for 24 weeks with an additional 24 weeks of interferon monotherapy (48-week treatment) was undergone by 42 1H patients and 5 non-1H patients. The combination therapy of interferon and ribavirin was administered for 24 weeks in 67 1H patients and 22 non-1H patients. Among the 1H patients, the HCV relapse rate was significantly higher in those receiving 24-week combination treatment than in those receiving 48-week treatment (78% versus 42%, [Formula: see text] ). Among the non-1H patients, no significant difference was found between them. Sustained virological response (SVR) rates were observed to decrease as the timing of HCV RNA disappearance was delayed. In spite of the small rate (16%), SVR was obtained from the patients who became negative for HCV RNA by week 24 (beyond week 12) only in those receiving 48-week treatment. In 1H patients, 24-week combination treatment followed by interferon monotherapy for 24 weeks was concluded to be the treatment offering the most hope among those that the medical insurance can be applied in Japan.

Journal Article↗
PubMed1999

Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-beta1a in relapsing-remitting multiple sclerosis. Prevention of Relapses and Disability by Interferon-beta1a Subcutaneously in Multiple Sclerosis.

The PRISMS (Prevention of Relapses and Disability by Interferon-beta1a Subcutaneously in Multiple Sclerosis) trial was a double-blind, randomized, multicenter, phase III, placebo-controlled study of interferon-beta1a in 560 patients from 22 centers in 9 countries with clinically definite or laboratory-supported relapsing-remitting multiple sclerosis. The patients were randomized to receive recombinant interferon-beta1a (Rebif), 22 microg (6 mIU), 44 microg (12 mIU), or placebo, given subcutaneously, three times weekly for 2 years. All patients underwent biannual proton density/T2-weighted magnetic resonance imaging scans to determine the overall magnetic resonance imaging disease activity and burden of disease, and a cohort of 205 patients had 11 initial monthly proton density/T2-weighted and gadolinium-enhanced/T1-weighted magnetic resonance imaging scans. Over the 2 years, the placebo group showed a progressive median increase in burden of disease of 10.9%, whereas the 22-microg group and 44-microg group showed median decreases of 1.2% and 3.8%, respectively. The number of T2 active lesions and percentage of scans showing T2 activity on the biannual scans were also significantly reduced in both treatment groups compared with placebo, with a clear dose-effect favoring the 44-microg dose over the 22-microg dose. In the subgroup undergoing initial monthly scanning, this reduction in activity became statistically significant 2 months after the start of treatment. These results provide strong, objective evidence to support the positive clinical results of reduction in relapses and delay in disease progression. In addition, they also demonstrate a significant dosage effect, favoring the 44-microg dose.

Adult↗
PubMed1991

Treatment with human gamma interferon of chronic hepatitis B: comparative study with alpha interferon.

A pilot study was designed to determine the tolerance and effectiveness of natural or recombinant gamma interferon in patients with chronic hepatitis B. Sixteen patients received 0.5 to 3.0 million units (MU) per day of gamma interferon (IFN-gamma) for 7 days. Nineteen chronic hepatitis B patients who were treated with 5-6 MU leukocyte-derived alpha interferon (IFN-alpha) daily served as controls. All completed the treatment schedule. IFN-gamma exerted mild, but significant inhibitory effects (P less than .05) on serum DNA polymerase levels. However, the changes were significantly less (P less than .001) than those seen with IFN-alpha therapy when compared with percent change from basal values. In contrast, serum 2', 5'-oligoadenylate synthetase (2-5 AS) activities were markedly enhanced to a similar extent during therapy with both IFNs. Serum beta 2-microglobulin values were significantly increased by administration with both IFNs, although higher values were seen with IFN-gamma. Five patients received 1 MU IFN-gamma for 28 consecutive days and their HBeAg levels similarly decreased as those seen in patients treated with IFN-alpha. Side effects seemed to be greater during IFN-gamma therapy than IFN-alpha despite the lower doses used. The antiviral effect on serum HBV levels appeared less with IFN-gamma than with IFN-alpha. Alternatively immunomodulatory functions may have been enhanced with IFN-gamma in patients with chronic HBV infection.

Adolescent↗
PubMed1985

Human beta:alpha but not gamma interferon binding site is a product of the chromosome 21 interferon action gene.

The binding of human interferons to their binding site(s) was measured by the amount of radioiodinated human beta interferon (HuIFNbeta) displaceable by unlabeled human beta, alpha, and gamma interferon (HuIFNbeta, alpha, and gamma). By this approach, HuIFNbeta and HuIFNalpha were found to interact with specific binding sites in cell membranes derived from human cells and mouse-human cell hybrids containing chromosome 21 as their only human chromosome. Specific binding was not observed with cell membranes derived from parental mouse cells or from mouse-human cell hybrids in subsequent generations that have lost human chromosome 21. Although the chromosome 21-positive mouse-human cell hybrids are sensitive to the antiviral effects of HuIFNbeta and HuIFNalpha, they are found to be insensitive to the antiviral effect of HuIFNgamma and to lack specific HuIFNgamma binding sites. These results suggest that the HuIFNbeta and HuIFNalpha but not HuIFNgamma binding sites are coded for by genes located on chromosome 21. The lack of a chromosome 21 gene dosage effect on the inducibility of the antiviral state by HuIFNgamma is consistent with this hypothesis.

Animals↗
PubMed1990

Antitumor effect of combination of murine recombinant interferon beta, murine recombinant interferon gamma and human recombinant interleukin-2 in MethA-bearing mice.

We have previously reported that the combination of murine recombinant interferon beta (Mu-rIFN beta) with murine recombinant interferon gamma (Mu-rIFN gamma) provided greater inhibition of tumor growth than did each one alone in MethA-bearing mice. In the present study the effect of addition of human recombinant interleukin-2 (Hu-rIL-2) to the combination of Mu-rIFN beta with Mu-rIFN gamma on tumor growth in BALB/c mice bearing syngeneic MethA fibrosarcoma was examined. Low doses of Hu-rIL-2 (5 x 10(3) U or 5 x 10(4) U at 3-day intervals) showed no antitumor activity, while a high dose of Hu-rIL-2 (5 x 10(5) U) showed profound growth inhibition. The administration of IL-2 (ranging between 5 x 10(3) U and 5 x 10(5) U) in addition to the combination of IFN beta and IFN gamma showed more augmented antitumor effects in a dose-dependent manner. Furthermore, the simultaneous administration of IL-2, IFN beta and IFN gamma had more effective therapeutic activity, compared with the sequential administration of interferons and IL-2. These findings indicated that IL-2 in combination with IFN beta and gamma was effective for cancer treatment.

Animals↗
PubMed1990

Antiproliferative effects of natural interferon beta alone and in combination with natural interferon gamma on human breast carcinomas in nude mice.

Nude mice bearing bilateral xenografts of human breast carcinoma cells (MCF-7 and BT20) were treated with 2 or 45-day cycles of intralesional (i.l.) injections of human natural interferon beta (nIFN-beta) alone or in combination with human natural interferon gamma (nIFN-gamma). The injections were administered to only 1 of the 2 tumors in each animal, thus making it possible to assess at the same time local therapeutic effects in the injected tumors and systemic effects in the contralateral ones. When n-IFN-beta was used as a single agent only mild local antitumor effects and virtually no systemic effects were observed. In contrast, the combined administration of nIFN-beta/nIFN-gamma produced marked antiproliferative effects, presumably as a result of the synergistic action of type I and type II IFNs. These effects ranged from complete regression documented histologically in 2 MCF-7 tumors to varying degrees of growth inhibition with persistence of residual microscopic or grossly detectable tumor. Local effects were more pronounced than systemic effects. The therapeutic efficacy of nIFN-beta proved to be greater than that of recombinant interferon beta (rIFN-beta). In MCF-7 tumors nIFN-beta appeared to be less effective than nIFN-alpha, whereas the opposite was true for BT20 tumors.

Animals↗
PubMed1990

Difference in effects of interferon-alpha and interferon-gamma on the induction of differentiation of retinoic acid-treated acute myeloid leukemia cells in primary culture.

We studied differentiation inducing effects of retinoic acid (RA), 1 alpha, 25-dihydroxyvitamin D3 (D3) and interferons (IFNs), alone and in combination, on fresh myeloid leukemic cells from 8 patients. RA not only induced the differentiation of leukemic cells in 5/8 cases, but potentiated differentiation by IFNs either in granulocytic or monocytic pathways. In particular, interferon-alpha enhanced granulocytic differentiation and interferon-gamma induced mono-macrophage differentiation of promyelocytic leukemic cells in the presence of RA. Differentiation induced by D3, alone or in combination with IFNs, was limited in all cases. RA plus IFNs might be an effective combination for differentiation therapy for some types of myeloid leukemia.

Cell Differentiation↗
PubMed1990

Recombinant bovine interferon-gamma, but not interferon-alpha, potentiates bovine neutrophil oxidative responses in vitro.

In this study we have addressed the in vitro effects of recombinant bovine interferon-gamma (rBoIFN-gamma) and interferon-alpha (rBoIFN-alpha 1) on oxidative functions of bovine neutrophils. Treatment with rBoIFN-gamma, but not rBoIFN-alpha 1, enhanced the luminol-dependent chemiluminescence (LDCL) response of bovine neutrophils to both opsonized zymosan particles and phorbol myristate acetate. Pre-incubation of neutrophils for 2 h at 39 degrees C with rBoIFN-gamma resulted in a 40% increase in both LDCL and release of hydrogen peroxide by neutrophils stimulated with opsonized zymosan. This enhancement was observed at doses ranging from 0.2 to 2000 units of rBoIFN-gamma per ml. In contrast to the results observed in the LDCL and hydrogen peroxide assays, preincubation of neutrophils with rBoIFN-gamma had no effect on the levels of superoxide anion released in response to opsonized zymosan. Pre-incubation with rBoIFN-gamma increased phorbol myristate acetate (PMA)-stimulated LDCL by 30%, although it had no effect on either superoxide anion or hydrogen peroxide release in response to PMA stimulation. Neither recombinant interferon directly elicited an oxidative burst from neutrophils in the absence of zymosan or PMA stimulation.

Animals↗
PubMed1989

Stimulation of microtubule assembly by recombinant human interferon-alpha and interferon-gamma.

Interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma) have been demonstrated to stimulate microtubule assembly measured in the in vitro assembly system. The process is substoichiometric occurring when the interferon concentrations are below that of tubulin. IFN-gamma is a more potent effector than IFN-alpha. The critical tubulin concentration describing microtubule assembly decreases from 1.5 mg/ml measured in the absence of added effector to 1.05 mg/ml and 1.3 mg/ml when measured in the presence of 2.16.10(-6) M IFN-gamma and 3.06.10(-6) M IFN-alpha, respectively.

Animals↗
PubMed1989

Interferon-alpha and interferon-gamma as regulators of human adult and newborn B-cell function.

The role of interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma) in the regulation of B-cell function was studied using highly purified tonsillar B-cells and unfractionated mononuclear cells from healthy adults and newborns. Recombinant IFN-gamma (rIFN-gamma) was found to enhance Staphylococcus aureus Cowan I (SAC)-induced proliferation of purified B-cells. Recombinant IFN-alpha (rIFN-alpha) neither enhanced nor inhibited the function of purified B-cells. However, when unfractionated mononuclear cells were studied, no enhancement in SAC- or pokeweed mitogen (PWM)-induced proliferation was found in response to these IFNs. In fact, the responses in these cultures were mainly inhibitory. The effects were dependent on the mitogen used for activation of the cells and on the source of the cells. The IFNs acted in a more inhibitory way in cultures stimulated with PWM than in those stimulated with SAC. In addition, they acted more suppressively in cord blood mononuclear cells (CBMCs) than in adult peripheral blood mononuclear cells. PWM was found to decrease CD4+/CD8+ T-cell ratio, and cells with suppressor function physiologically dominate among CBMCs. Thus, the effect of these interferons on B-cell function seems to depend on the magnitude of suppressor cell function among the cell population.

B-Lymphocytes↗
PubMed2004

A C-terminal basic amino acid motif of Zaire ebolavirus VP35 is essential for type I interferon antagonism and displays high identity with the RNA-binding domain of another interferon antagonist, the NS1 protein of influenza A virus.

The ebolavirus VP35 protein antagonizes the cellular type I interferon response by blocking phosphorylation of IRF-3, a transcription factor that turns on the expression of a large number of antiviral genes. To identify the domain of VP35 responsible for interferon antagonism, we generated mutations within the VP35 gene and found that a C-terminal basic amino acid motif is required for inhibition of ISG56 reporter gene expression as well as IFN-beta production. Remarkably, this basic amino acid motif displayed high sequence identity with part of the N-terminal RNA-binding domain of another interferon-antagonist, the NS1 protein of influenza A virus.

Amino Acid Motifs↗
PubMed1999

NFkappaB activation is required for interferon regulatory factor-1-mediated interferon beta induction.

The interferon regulatory factor 1 (IRF-1) acts as a transcriptional inducer of the interferon beta (IFN-beta) gene and interferon-stimulated genes. Here we report that IRF-1-mediated IFN-beta induction depends on NFkappaB activity. IRF-1 by itself initiates NFkappaB activation by inducing a reduction in cellular MAD3/IkappaBalpha, an inhibitor of NFkappaB. After nuclear translocation, NFkappaB synergizes with IRF-1 on the cis-elements positive regulatory domain (PRD)II and PRDI/III to induce transcription of the IFN-beta gene. In contrast with IFN-beta transcription induced by dsRNA or virus, c-Jun/ATF-2 binding to PRDIV is not involved. Recombinant MAD3/IkappaBalpha is phosphorylated in vitro by extracts from IRF-1-expressing cells. IRF-1-dependent MAD3/IkappaBalpha degradation is not detectable in cells expressing a dominant negative mutant of the protein kinase PKR, suggesting that PKR mediates MAD3/IkappaBalpha degradation.

Binding Sites↗
PubMed1996

Cooperative role of interferon regulatory factor 1 and p91 (STAT1) response elements in interferon-gamma-inducible expression of human indoleamine 2,3-dioxygenase gene.

Interferon (IFN)-gamma induces the expression of the indoleamine 2, 3-dioxygenase (INDO) gene in human cells, which plays a role in the inhibitory effect of IFN-gamma on intracellular pathogens and on cell proliferation. Earlier studies established that the IFN-gamma-inducible expression of the INDO gene was dependent on two upstream elements: (i) a 14-base pair sequence homologous to an interferon-stimulated response element (ISRE) sequence found in IFN-alpha-inducible genes and (ii) a 9-base pair palindromic sequence (palindromic element (PE) II) homologous to an interferon-gamma-activated site (GAS) element found in IFN-gamma-inducible genes. A second GAS element (PE I), between ISRE and PE II, was ineffective in supporting a response to IFN-gamma. Studies were carried out to determine the distinction between the two GAS elements and the relative role of the two elements (ISRE and PE II) required for a response to IFN-gamma. The PE I element was able to form a complex with IFN-gamma-activated p91 (STAT1) factor but with lower efficiency than the complex formed with PE II sequence. However, switching the positions of PE I and II sequences in reporter plasmid constructs (containing chloramphenicol acetyltransferase gene) showed that both PE I and PE II were able to support a response to IFN-gamma if located at the position of PE II but not at the position of PE I. Increasing the distance between the ISRE and PE II also affected the level of response, suggesting that the relative position of the two elements is important for optimal stimulus. To explore whether an interaction between the IFN-gamma-regulated factors (IRF-1 and p91) binding to the ISRE and PE II might be important, we tested whether the ISRE sequence could be replaced by another response element, NF-kappaB. The plasmid construct with NF-kappaB element in place of the ISRE was responsive to IFN-gamma, indicating that an interaction between the IRF-1 and p91 factors was not required. The results indicate that the response of INDO gene to IFN-gamma depends on a cooperative role of IFN-gamma-responsive factors binding to the ISRE and GAS elements.

Base Sequence↗