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At least 469 records · Page 26Linked to original sources
PubMed1998

Interferon-beta is required for interferon-alpha production in mouse fibroblasts.

The type I interferons--interferon-alpha (IFN-alpha) and interferon-beta (IFN-beta)--are critical for protection against viruses during the acute stage of viral infection [1,2]. Furthermore, type I interferons have been implicated as important mediators in the regulation of lymphocyte development [3], immune responses [4,5] and the maintenance of immunological memory of cytotoxic T cells [6,7]. The different IFN-alpha subtypes are encoded by 12 genes in the mouse [8] whereas IFN-beta is encoded by only one gene [9]. IFN-alpha and IFN-beta have a high degree of sequence homology and are thought to interact with the same surface receptor on target cells [10,11]. As an approach to analysing the different biological functions of IFN-alpha and IFN-beta, we have generated a mouse strain with an inactivated IFN-beta gene. We report here that embryonic fibroblasts from such mice produce neither IFN-beta nor IFN-alpha upon Sendal virus infection, whereas the production of IFN-alpha by leukocytes from the same strain of mice is intact. IFN-alpha production in embryonic fibroblasts from IFN-beta-/- mice could be rescued by 'priming' the cells using exogenous IFN-beta. These results imply a unique role for IFN-beta in the induction of type I interferons in peripheral tissues.

Animals↗
PubMed2001

High-Dose interferon-alpha2b plus ribavirin for retreatment of interferon-nonresponsive patients infected with genotype 1 hepatitis C virus.

Ten patients with interferon-nonresponsive chronic hepatitis C were treated with high-dose interferon-alpha2b (IFN-alpha2b; 20 MU/day for two days, then 3 MU/day for 24 weeks, followed by 3 MU three times weekly for 24 more weeks) plus ribavirin (1000-1200 mg/day). End-of-treatment virologic responses occurred in 50% of cases and sustained virologic responses in 37.5%. Hepatitis C virus RNA decreased significantly (2.15 logs; P < 0.0001) after the two 20-MU interferon doses but rebounded when the interferon dose was lowered to 3 MU/day. Thereafter, hepatitis C virus RNA showed a progressive, significant decrease, most notably at week 10 (3.3 logs; P = 0.001). Patients with a sustained response exhibited a more pronounced hepatitis C virus RNA decrease, especially from weeks 3 to 8 (P = 0.036). Two patients discontinued therapy because of adverse events, and one patient required a ribavirin dose reduction. Retreatment with an initial high-dose IFN-alpha2b plus ribavirin significantly reduces viral load in genotype 1-infected, interferon-nonresponsive patients.

Adult↗
PubMed2001

A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C.

This international, randomized, active-controlled, parallel-group, double-blind dose-finding study compared peginterferon alfa-2b (PegIntron) to interferon alfa-2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three-times-weekly (TIW) interferon alfa-2b dose (3 MIU) or the once-weekly (QW) peginterferon alfa-2b (0.5, 1.0, or 1.5 microg/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 peginterferon alfa-2b doses significantly (P < or =.042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow-up, as compared with interferon alfa-2b. Unlike the end-of-treatment virologic response, the sustained virologic response rate was not dose-related above 1.0 microg/kg peginterferon alfa-2b because of a higher relapse rate among patients treated with 1.5 microg/kg peginterferon alfa-2b, particularly among patients infected with genotype 1. All 3 peginterferon alfa-2b doses decreased liver inflammation to a greater extent than did interferon alfa-2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, peginterferon alfa-2b maintained (0.5 microg/kg) or surpassed (1.0, 1.5 microg/kg) the clinical efficacy of interferon alfa-2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 microg/kg peginterferon alfa-2b in patients infected with genotype 1 and high viral levels warrants further evaluation.

Adult↗
PubMed1983

An interferon-beta-like or interferon-inducing protein released by mitogen-stimulated human leukocytes.

Human peripheral blood leukocytes were treated with concanavalin A (Con A) to produce interferon gamma (HuIFN-gamma). On gel filtration this interferon eluted as a protein with a molecular weight of 45000. In addition to this, the culture supernatant contained an interferon-like protein of apparent molecular weight 22000 (22K factor). The antiviral activity of this protein was neutralizable by a highly specific antibody to HuIFN-beta. Yet, the 22K factor differed from classical HuIFN-beta in several characteristics: lack of activity on certain homologous and heterologous cells which are sensitive to HuIFN-beta; lack of affinity for zinc-chelate and Con A-Sepharose columns; failure to bind to an anti-HuIFN-beta antibody column. Moreover, a specific antiserum raised against the 22K factor did not neutralize HuIFN-beta. Two alternative explanations of these findings are proposed: (i) the 22K factor is an interferon whose molecular structure resembles that of the known HuIFN-beta but it is not identical to it, or (ii) the 22K factor is not an interferon but a protein that can induce the production of HuIFN-beta in certain lines of fibroblastoid cells.

Concanavalin A↗
PubMed2004

Modifications of haematological series in patients co-infected with human immunodeficiency virus and hepatitis C virus during treatment with interferon and ribavirin: differences between pegylated and standard interferon.

Therapy with interferon and ribavirin for hepatitis C virus (HCV) infection induces a decrease in several haematological population counts. It is unclear whether haematological toxicity is more severe in patients co-infected with HCV and human immunodeficiency virus (HIV). This study analysed the evolution of haematological population counts during and after interferon and ribavirin therapy for chronic HCV infection. Eleven patients co-infected with HIV and HCV and treated with pegylated interferon plus ribavirin, and ten treated with standard interferon plus ribavirin, were analysed. With reference to baseline values, neutrophil counts decreased by an average of 45% (range 18-67%), total lymphocytes by 50% (16-63%), CD4 lymphocytes by 54% (16-61%), haemoglobin by 9% (5-16%) and platelets by 31% (16-45%). The nadir of the decrease was reached in the first weeks of therapy and was maintained while patients were receiving treatment. The reduction in all series was higher with pegylated interferon. Patients recovered their baseline counts after finishing the treatment. No cases of haemorrhage or outstanding infection were detected during follow-up.

AIDS-Related Opportunistic Infections↗
PubMed1981

Hypoglycemia in mice injected with interferon inducers is not mediated by interferon.

Injection of mice with several viral and nonviral inducers of interferon resulted in a marked hypoglycemia. Interferon is not responsible for this effect since inoculation of a potent antiserum to interferon (which neutralized the endogenous interferon) did not prevent hypoglycemia and administration of potent interferon preparations did not lower blood sugar. Hypoglycemia induced by Newcastle disease virus and polyriboinosinic-polyribocytidylic acid was further exacerbated by injection of insulin.

Animals↗
PubMed1991

Interferon alpha-2b treatment of chronic posttransfusion non-A, non-B/C hepatitis: long-term outcome and effect of increased interferon doses in non-responders.

The biochemical and histological long-term outcome of interferon alpha-2b treatment for chronic posttransfusion non-A, non-B/C hepatitis was evaluated in a randomized study. 4/19 treated patients had a sustained response with normal serum alanine aminotransferases (s-ALAT) levels during follow-up, at present for 18-20 months after the end of interferon treatment. None of 11 responders with biochemical relapse normalized their s-ALAT levels during 1 year follow-up after treatment. Histological changes were assessed by a scoring system. The scores for portal inflammation, piecemeal necrosis and fibrosis were essentially unchanged in all treated patients between biopsies taken at the end of treatment and 1 year later. Six non-responders to 3 million units (MU) alpha-2b interferon thrice weekly (t.i.w.) were given 6 MU t.i.w. for at least 8 weeks. None normalized the s-ALAT levels during treatment with the higher dose, instead the side effects were much more pronounced, an obstacle to the usefulness of higher interferon doses. The biochemical non-responders had higher pretreatment histologic inflammation scores indicating a more severe infection. They also had a higher body weight and seemed to have prominent macrovesicular steatosis more often than responders, a finding that could contribute to raised aminotransferases, thereby in some of the non-responders, masking a positive biochemical effect of interferon treatment.

Adult↗
PubMed2005

Superiority of standard interferon-alpha2b compared to pegylated interferon-alpha2b (12 kDa) in a hemodialysis patient with chronic hepatitis C?

INTRODUCTION: Hepatitis C virus (HCV) infection represents an important problem for hemodialysis patients. Interferon-alpha (IFN-alpha) three times per week has been shown to clear HCV RNA in a substantial proportion of renal transplant candidates, and may thereby prevent the deleterious effect of immunosuppressive treatment on progression of liver disease in HCV-positive patients after renal transplantation. Data on the efficacy of the new pegylated interferons in hemodialysis patients are limited and general recommendations are absent. CASE: A 41-year-old Caucasian man infected with hepatitis C genotype 1b was admitted with a history of renal transplantation in 1990, and reintroduced hemodialysis in 1997 because of chronic rejection. Antiviral therapy with pegylated interferon-alpha2b (120 microg/oiw) and ribavirin (400 mg/tiw) was initiated. A virological and biochemical response with undetectable HCV-RNA was evident already after six weeks. Two weeks later, however, HCV-RNA became detectable again with 18.000 IU/ml. The treatment regimen was changed to standard-IFN-alpha2b (3 MU/tiw). Shortly thereafter, ribavirin had to be withdrawn because of severe anemia. After three weeks, hemoglobin level rebounded to values higher than 10 g/dl and a lower dose of ribavirin (200 mg/tiw) could be reintroduced. Virological and biochemical response occurred after switching to standard interferon-alpha2b within three months with good tolerance of antiviral combination treatment until the end of 48 weeks of therapy. The patient remained HCV-RNA-negative throughout follow-up of 36 weeks. ALT levels are still within normal limits and the patient is now waiting for a kidney transplantation. CONCLUSION: Considering the treatment course of this patient, IFN-alpha2b three times per week directly after hemodialysis seems to be superior to pegylated interferon-alpha2b once weekly in this case. The role of pegylated IFN-alpha2a for dialysis patients remains to be investigated.

Adult↗
PubMed1990

Protection from carcinogen-induced murine bladder carcinoma by interferons and an oral interferon-inducing pyrimidinone, bropirimine.

Interferons (IFNs) have established activities as antivirals and inhibitors of viral and transplantable tumors. To establish whether IFNs or their inducers can affect induction of carcinogenesis in vivo, the bladder-specific carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) was administered in the diet at 0.11 or 0.13% (w/w) to female C3H/He mice beginning at 7 weeks of age. Mice treated with the IFN-inducing bropirimine [2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone] i.p. twice a week for 14 weeks starting on day 30 of start of FANFT feeding developed fewer transitional cell carcinomas (TCC) than mice treated with the vehicle. Bropirimine (200 mg/kg twice a week) orally resulted in even greater effectiveness: 6 of 43 bladders with TCC for bropirimine-treated mice versus 24 of 39 for control glycine buffer-treated mice (P less than 0.01, x2 test). Mice treated i.p. daily on days 29 through 210 with 5,000 units of beta interferon (specific activity, 2.0 x 10(8) units/mg) had 0 of 15 TCC while control mice had 7 of 13 TCC (P less than 0.001). Bladders of untreated mice were also significantly heavier than those of beta interferon- or bropirimine-treated mice. This dose of IFN treatment was confirmed as effective in a second experiment, in which mice were treated daily on days 30-223 with 5,000 units alpha/beta interferon (specific activity, 1.2 x 10(7) units/mg). This resulted in 4 of 25 bladders with TCC versus 24 of 39 for control mice (P less than 0.001). A higher dose of IFN (50,000 units alpha/beta interferon daily) was toxic; 24 of 30 mice died within 2 months. IFN and an IFN inducer, bropirimine, inhibited development and progression of FANFT-induced bladder TCC in vivo and thus may have roles as chemopreventive modalities.

Animals↗
PubMedDate not supplied

Anticellular activities of human fibroblast interferon beta and human recombinant interferon gamma. Cytologic changes in a cervical cancer cell line.

The cellular changes in a human cervical squamous-cell-cancer cell line (SKG-IIIb) were investigated after treatment with human recombinant interferon gamma and human fibroblast interferon beta. Cytoplasmic changes characterized by elongation, vacuolization and blurring of cytoplasmic borders appeared relatively early in both treatment groups. After two days of treatment with interferon gamma, the cells began to aggregate and to form pearl-like structures in the center of these aggregates; frequently seen were isolated cells with an eosinophilic cytoplasm and a pyknotic nucleus, similar to keratinizing cells. After six days of treatment with interferon beta, on the other hand, more than 20% of the cells began to show nuclear changes, including remarkable pleomorphism, multilobulation and multinucleation. The differences in biologic activities between the two interferons are discussed on the basis of these observations.

Cell Line↗
PubMed1994

cDNA sequence identity for the type I interferon receptor subunit from cell lines of widely differing responsiveness to interferon.

Melanoma cell lines exhibit strikingly different sensitivity to the antiproliferative effects of interferon. cDNAs encoding the Type I interferon receptor subunit were amplified by polymerase chain reaction, using as template RNA isolated from three melanoma cell lines displaying greater than 100 fold range in their sensitivity to the antiproliferative effects of IFN-beta. Comparison of the cDNA sequences obtained with the published cDNA sequence from the highly interferon-sensitive lymphoid cell line Daudi revealed only one base change that leads to a conservative amino acid substitution. It is concluded that the cellular differences in responsiveness to interferon, of the melanoma cell lines tested, do not arise from the expression of variants of the cloned Type I interferon receptor subunit.

Base Sequence↗
PubMed1999

Lipopolysaccharide inhibits virus-mediated induction of interferon genes by disruption of nuclear transport of interferon regulatory factors 3 and 7.

We have studied the effects of lipopolysaccharide (LPS) on the Newcastle disease virus (NDV)-mediated induction of cytokine genes expression. Raw cells treated with LPS before or after virus infection showed down-regulation in the expression of interferon A and, to a lesser extent, interferon B genes. In contrast, induction of the interleukin (IL)-6 gene was enhanced. The effects of LPS were not a result of the suppression of virus replication, because the transcription of viral nucleocapsid gene was not affected. Consistent with these findings, LPS also suppressed the NDV-mediated induction of chloramphenicol acetyltransferase reporter gene driven by murine interferon A4 promoter in a transient transfection assay. Furthermore, LPS inhibited virus-mediated phosphorylation of interferon regulatory factor (IRF)-3 and the consequent translocation of IRF-3 from cytoplasm to nucleus. The LPS-mediated inhibition of IFNA gene expression was much weaker in infected Raw cells that constitutively overexpressed IRF-3. The nuclear translocation of IRF-7 in infected cells was also inhibited by LPS. These data suggest that LPS down-regulates the virus-mediated induction of IFNA genes by post-translationally targeting the IRF-3 and IRF-7 proteins.

Animals↗
PubMed1998

Immune response to mouse mammary tumor virus in mice lacking the alpha/beta interferon or the gamma interferon receptor.

Mouse mammary tumor virus (MMTV) is a retrovirus which induces a strong immune response and a dramatic increase in the number of infected cells through the expression of a superantigen (SAg). Many cytokines are likely to be involved in the interaction between MMTV and the immune system. In particular, alpha/beta interferon (IFN-alpha/beta) and gamma interferon (IFN-gamma) exert many antiviral and immunomodulatory activities and play a critical role in other viral infections. In this study, we have investigated the importance of interferons during MMTV infection by using mice with a disrupted IFN-alpha/beta or IFN-gamma receptor gene. We found that the SAg response to MMTV was not modified in IFN-alpha/betaR(0/0) and IFN-gammaR(0/0) mice. This was true both for the early expansion of B and T cells induced by the SAg and for the deletion of SAg-reactive cells at later stages of the infection. In addition, no increase in the amount of proviral DNA was detected in tissues of IFN-alpha/betaR(0/0) and IFN-gammaR(0/0) mice, suggesting that interferons are not essential antiviral defense mechanisms during MMTV infection. In contrast, IFN-gammaR(0/0) mice had increased amounts of IL-4 mRNA and an altered usage of immunoglobulin isotypes with a reduced frequency of IgG2a- and IgG3-producing cells. This was associated with lower titers of virus-specific antibodies in serum early after infection, although efficient titers were reached later.

Animals↗
PubMed1999

Functional analysis of human herpesvirus 8-encoded viral interferon regulatory factor 1 and its association with cellular interferon regulatory factors and p300.

Human herpesvirus 8/Kaposi sarcoma-associated virus (HHV-8/KSHV) contains, in addition to genes required for viral replication, a unique set of nonstructural genes which may be part of viral mimicry and contribute to viral replication and pathogenesis in vivo. Among these, HHV-8 encodes four open reading frames (ORFs) that showed homology to the transcription factors of the interferon regulatory factor (IRF) family. The ORF K9, viral IRF 1 (vIRF-1), has been cloned, and it was shown that, when overexpressed, it down modulates the interferon-mediated transcriptional activation of the interferon-stimulated gene 15 (ISG 15) promoter, and the role of vIRF-1 in viral mimicry was implied. However, the molecular mechanism of this effect has not been clarified. Here, we extend this observation and show that vIRF-1 also downregulates the transcriptional activity of IFNA gene promoter in infected cells by interfering with the transactivating activity of cellular IRFs, including IRF-1 and IRF-3. We further show that ectopic expression of vIRF-1 in NIH 3T3 cells confers resistance to tumor necrosis factor alpha-induced apoptosis. While vIRF-1 is unable to bind DNA with the same specificity as cellular IRFs, we demonstrate by in vitro binding assay that it can associate with the family of cellular IRFs, such as IRF-1 and the interferon consensus sequence binding protein. vIRF-1 interaction domain was localized between amino acids (aa) 152 and 243. While no binding between the full-size IRF-3 and vIRF-1 could be detected by the same assay, we show that vIRF-1 also targets the carboxy-terminal region (aa 1623 to 2414) of the transcriptional coactivator p300 which could also bind IRF-3 and IRF-1. These results demonstrate that vIRF-1 can modulate the transcription of the IFNA genes by direct heterodimerization with members of the IRF family, as well as by competitive binding with cellular transcription factors to the carboxy-terminal region of p300.

3T3 Cells↗
PubMed1992

Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes.

The promoter regions of many interferon-inducible genes share a short DNA sequence motif, termed the interferon consensus sequence (ICS) to which several regulatory proteins bind. A murine cDNA which encodes an ICS binding protein has been reported (M-ICSBP). The cloning of the human homologue of ICSBP (H-ICSBP) is described. H-ICSBP shares high sequence homology with its murine cognate. The derived sequence of H-ICSBP reveals restricted homology within the first 120 amino acids to three other interferon regulatory factors, IRF-1, IRF-2, and ISGF3 gamma. Truncated ICSBP lacking the first 33 amino-terminal amino acids fails to bind to the ICS, indicating that at least part of the DNA binding domain is located within the well conserved amino terminus. H-ICSBP is expressed exclusively in cell lines of hematopoietic origin. The results of transient transfection assays carried out either in hematopoietic or nonhematopoietic cells suggest that ICSBP acts as a negative regulatory factor on ICS-containing promoters. Furthermore, either interferon-gamma (IFN-gamma) or IFN-beta can alleviate the repression mediated by ICSBP. Therefore, ICSBP may be involved in maintaining submaximal transcriptional activity of IFN-inducible genes in hematopoietic cells. IFN treatment would then alleviate repression allowing maximal transcriptional activity of these genes.

Amino Acid Sequence↗
PubMedDate not supplied

[The interferon status and circulating immunoglobulins during the interferon therapy of respiratory papillomatosis in children].

Studies on the functional activity of interferon (IF) system (interferon status and serum immunoglobulins levels) and its changes in the course of interferon therapy of juvenile respiratory papillomatosis are presented. The initial disorders in alpha-IF production and levels of circulating IF came to normal after interferon therapy. Correlative changes of the following parameters occurred: a decrease in the level of circulating IF and IgM and simultaneous increase in the level of alpha-IF and IgG which, however, did not always correlate strictly with the course of the disease and the kind of preparation used.

Child↗
PubMed1987

Phase II study of recombinant human interferon gamma (S-6810) on renal cell carcinoma. Summary of two collaborative studies. Recombinant Human Interferon Gamma (S-6810) Research Group on Renal Cell Carcinoma.

Seventeen institutions in Japan evaluated the antitumor activity of recombinant human interferon gamma (S-6810) as a new modality for advanced renal cell carcinoma. The response rate for 32 evaluable patients who received continuous daily administration of 8 X 10(6) U/m2 to 12 X 10(6) U/m2 of interferon for 4 weeks was 9.4%. Six of 30 patients (20%) were demonstrated responders in the case of the intermittent administration of 40 X 10(6) U/m2 of interferon on each of days 1 to 5, 15 to 19, 29, 31, 33, 43, 45, and 47 over an 8-week period. One of the responders achieved a complete response (CR). The patients tolerated this dose of interferon gamma well. Sites that responded to treatment were the lungs, lymph nodes, and brain. Major adverse effects included fever (86.8% of patients), anorexia (67.1%), fatigue (53.9%), and leukopenia (42.1%). No life-threatening side effects appeared. High doses of recombinant human interferon gamma have an antitumor activity against renal cell carcinoma.

Adult↗
PubMedDate not supplied

Measurement of recombinant interferon levels by high performance immunoaffinity chromatography in body fluids of cancer patients on interferon therapy.

The technique of high performance immunoaffinity chromatography was used to measure the levels of recombinant interferon in chronic lymphocytic leukaemia patients enrolled in a phase II recombinant interferon clinical trial. The technique employed a short high pressure chromatography column packed with minute glass beads which had monoclonal antibody, directed against recombinant alpha interferon, immobilized to their surface. This system was used to measure interferon levels in a variety of different human body fluids. A good correlation was found when interferon levels, detected by chromatographic separation, were compared to levels obtained by a conventional radioimmunoassay.

Adult↗