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At least 1,531 records · Page 85Linked to original sources
PubMed2000

Eradication of hepatitis C virus 1b by interferon in a health care worker with acute hepatitis following needlestick transmission from a patient with chronic hepatitis C unresponsive to interferon.

Hepatitis C virus (HCV) was successfully eradicated by a short course of interferon (IFN) therapy in a nurse with acute HCV infection from a needlestick accident. The source patient had chronic hepatitis C and was a nonresponder to IFN therapy. The HCV genotype was 1b in patients, and a single point mutation (H-->R in amino acid 2218) was observed in the IFN sensitivity-determining region of the nonstructural 5A gene, in comparison with sequences of HCV-J, in HCV RNA from both the source patient (before and after IFN therapy) and the recipient (before IFN therapy). Though the strain transmitted was believed to be IFN-resistant in the patient with chronic hepatitis, the patient with acute hepatitis had a sustained response.

Acute Disease↗
PubMed2001

Monitoring virological responses to interferon-ribavirin and interferon monotherapy of chronic hepatitis C re-treated due to relapse or non-response.

Adding the nucleoside analog ribavirin (RBV) to interferon (IFN) for treatment of HCV has improved the sustained response rates, but the mechanism by which RBV mediates viral clearance is not fully understood. In this study, a highly sensitive method (Codes Amplicor HCV Monitor) was used to monitor the early (first 12 weeks of therapy) and long-term virological response in 20 patients who were treated first with IFN and later, due to non-sustained response, with IFN-RBV. All 10 IFN relapsers displayed a prompt virological response at week 4 to both IFN and IFN-RBV therapy; nine of them showed a sustained response to IFN-RBV. Out of 10 IFN non-responders, five showed a sustained response to IFN-RBV. Four of these were HCV RNA-negative at week 4 of IFN-RBV therapy and two of them had a transient early virological response (RNA-negative at weeks 4-8) to IFN alone. Overall, of the 14 patients (nine IFN relapsers, five IFN non-responders) with a sustained response to IFN-RBV, 11 and 13 had HCV RNA below 2000 copies/ml at week 4 of IFN and IFN-RBV, respectively, as compared with one and one of six patients without a sustained response to IFN-RBV (p < 0.02). Thus, addition of RBV to IFN increased both viral clearance during the first 12 weeks of therapy and the rate of sustained response. Loss of viremia at week 4 of IFN was associated with a sustained response to IFN-RBV and was seen in 11 of 13 patients (85%) with genotypes 2 or 3, as compared with one of seven patients (14%) with genotype 1 (p = 0.0044).

Adult↗
PubMed1989

Application of Namalva interferon-alpha monoclonal antibodies for purification and enzyme immunoassay of interferon-alpha.

Namalva (or Namalwa) interferon (IFN)-alpha was partially purified using a combination of conventional methods and modified acid-ethanol extraction. Four mouse monoclonal antibodies against Namalva IFN-alpha were prepared by hybridoma technology after immunization with Namalva IFN-alpha thus purified. Three of these monoclonal antibodies recognized the same or a similar epitope on Namalva IFN-alpha. One of these antibodies was paired with the fourth recognizing a different epitope and used respectively as enzyme-conjugated antibody and solid-phase antibody in our one step enzyme immunoassay (EIA) for IFN-alpha. This assay is simple and was able to detect as little as 5 pg of IFN-alpha in 100 microliters of sample in the short time of 5 hr. There was a good correlation between the EIA and bioassay. The use of one of the monoclonal antibodies as an immunoadsorbant to purify Namalva IFN-alpha is also described.

Animals↗
PubMed1997

Intracellular antimicrobial activity in the absence of interferon-gamma: effect of interleukin-12 in experimental visceral leishmaniasis in interferon-gamma gene-disrupted mice.

Despite permitting uncontrolled intracellular visceral infection for 8 wk, interferon-gamma (IFN-gamma) gene knockout (GKO) mice infected with Leishmania donovani proceeded to reduce liver parasite burdens by 50% by week 12. This late-developing IFN-gamma-independent antileishmanial mechanism appeared to be dependent largely on endogenous tumor necrosis factor-alpha (TNF-alpha): L. donovani infection induced TNF-alpha mRNA expression in parasitized GKO livers and neutralization of TNF-alpha reversed control at week 12.7 d of treatment of infected GKO mice with interleukin-12 (IL-12) readily induced leishmanicidal activity and also partially restored the near-absent tissue granulomatous response, observations that for the first time expand the antimicrobial repertoire of IL-12 to include IFN-gamma-independent effects. The action of IL-12 against L. donovani was TNF-alpha dependent and required the activity of inducible nitric oxide synthase. These results point to the presence of an IFN-gamma-independent antimicrobial mechanism, mediated by TNF-alpha, which remains quiescent until activated late in the course of experimental visceral leishmaniasis. However, as judged by the effect of exogenous IL-12 this quiescent mechanism can readily be induced to rapidly yield enhanced intracellular antimicrobial activity.

Animals↗
PubMed2000

Rel induces interferon regulatory factor 4 (IRF-4) expression in lymphocytes: modulation of interferon-regulated gene expression by rel/nuclear factor kappaB.

In lymphocytes, the Rel transcription factor is essential in establishing a pattern of gene expression that promotes cell proliferation, survival, and differentiation. Here we show that mitogen-induced expression of interferon (IFN) regulatory factor 4 (IRF-4), a lymphoid-specific member of the IFN family of transcription factors, is Rel dependent. Consistent with IRF-4 functioning as a repressor of IFN-induced gene expression, the absence of IRF-4 expression in c-rel(-/-) B cells coincided with a greater sensitivity of these cells to the antiproliferative activity of IFNs. In turn, enforced expression of an IRF-4 transgene restored IFN modulated c-rel(-/-) B cell proliferation to that of wild-type cells. This cross-regulation between two different signaling pathways represents a novel mechanism that Rel/nuclear factor kappaB can repress the transcription of IFN-regulated genes in a cell type-specific manner.

Animals↗
PubMed2003

Type I interferon induction pathway, but not released interferon, participates in the maturation of dendritic cells induced by negative-strand RNA viruses.

Signaling through toll-like receptors (TLRs) is essential for dendritic cell (DC) maturation induced by bacteria and other pathogens. The mechanism for virus-induced DC maturation is not known. By use of pairs of live viruses with different abilities to induce the interferon (IFN) pathway, a strong correlation between DC maturation and the ability of the virus to induce type I IFN synthesis was demonstrated. The secreted IFN was not necessary, nor was it sufficient to induce full DC maturation. Intracellular viral replication is necessary for this process, and the transcription factor nuclear factor-kappaB was crucial for cytokine induction. The double-stranded RNA-dependent protein kinase was not essential for DC maturation. Similar to TLR-induced DC maturation, after virus infection, separate pathways for the induction of cytokine secretion and the up-regulation of major histocompatibility complex and costimulatory molecules were activated. It was demonstrated that these pathways have different sensitivities to the presence of viral stimulus.

Animals↗
PubMed2001

The interferon-inducible Stat2:Stat1 heterodimer preferentially binds in vitro to a consensus element found in the promoters of a subset of interferon-stimulated genes.

Regulated expression of type I interferon (IFN)-stimulated genes (ISG) requires the binding of the signal transducer and activator of transcription (Stat) complexes to enhancer elements located in the ISG promoters. These enhancer elements include the IFN-stimulated response element (ISRE) and the palindromic IFN-gamma activation site (GAS) element. Regulated expression of ISRE containing ISG depends on IFN-stimulated gene factor 3 (ISGF3), a heterodimer involving Stat1 and Stat2 in association with a DNA-binding adapter protein, p48/IFN regulatory factor-9 (IRF-9). Several GAS binding Stat complexes involving Stat1, Stat3, Stat4, and Stat5 have been described, but their contribution to GAS-dependent ISG expression remains to be established. We and others previously identified an IFN-alpha-inducible Stat2:1 heterodimer that exhibits binding to the GAS element of the IRF-1 gene. These previous studies raise the possibility that Stat2:1 may participate in the transcriptional activation of the subset of ISG containing GAS elements. To address this question, we performed a PCR-assisted binding site selection procedure to define the Stat2:1 recognition sequence. The data reveal that Stat2:1 preferentially binds to a palindromic sequence similar to the consensus GAS element found in the promoter of several ISG. Our results establish that in addition to the classic complex formation involving Stat2, Stat1, and p48 associations, Stat2:1 heterodimers are formed in response to IFN treatment that may play an important role in the transcriptional regulation of certain ISG.

Base Sequence↗
PubMed2002

The increase in levels of interferon-inducible proteins p202a and p202b and RNA-dependent protein kinase (PKR) during myoblast differentiation is due to transactivation by MyoD: their tissue distribution in uninfected mice does not depend on interferons.

The murine 200 family proteins p202a, p202b, and p204, and also RNA-dependent protein kinase (PKR) are inducible by interferons (IFNs). p202a, p202b, and p204 modulate the activity of a large variety of transcription factors and also are involved in muscle differentiation. PKR is a multifunctional serine/threonine kinase, which is involved in antiviral defense and cell growth control and in the response to various stress signals. We reported earlier that the level of p204 increases during cultured C2C12 myoblast differentiation to myotubes in consequence of transactivation by the skeletal muscle-specific MyoD protein. The levels of p202a, p202b, and PKR also increase during the differentiation. We report here that these increased protein levels also are due to the transactivation of their genes by MyoD. This is made possible by the occurrence in each of these genes of at least six E boxes, which are recognition sites for MyoD. We also show that the distribution of the p204, p202a, p202b, and PKR proteins in five tissues of adult C129 mice is the same in wild-type mice and mice lacking the IFN-alpha, IFN-beta, and IFN-gamma receptors. This indicates that the synthesis and distribution of these proteins in uninfected adult mice are not affected by endogenous IFNs.

Animals↗
PubMed1982

Autoantibodies against human beta interferon following treatment with interferon.

Recently we reported the appearance of human beta interferon (HuIFN-beta) neutralizing antibodies in a patient with a nasopharyngeal carcinoma treated successfully with a preparation of HuIFN-beta. This was the first report presenting evidence for antigenicity of IFN in an homologous system. In the present report we asked whether the unusual appearance of antibodies was due to a genetic defect of the patient's cells to produce HuIFN-beta or whether the patient's cells produce an antigenically different variant of HuIFN-beta. We demonstrate that a fibroblast cell strain established from this patient produces HuIFN-beta which does not from a serological standpoint react differently from the HuIFN-beta preparation administered. The conclusion is drawn that the antibodies against therapeutic HuIFN-beta are reacting like autoantibodies with the patient's own HuIFN-beta.

Autoantibodies↗
PubMed1982

Mechanism of interferon action: eIF-2 alpha phosphatase in interferon-treated mouse fibroblasts is double-stranded RNA independent.

The effect of double-stranded RNA on the dephosphorylation of purified, 32P-labeled eIF-2 was examined in cell-free extracts prepared from interferon-treated mouse L929 cells. Dephosphorylation of the alpha subunit of eIF-2 occurred at comparable rates in the presence and in the absence of reovirus dsRNA. By contrast, the beta subunit of eIF-2 was not dephosphorylated to any significant extent in either the presence or the absence of dsRNA. These results indicate that the enhanced phosphorylation of eIF-2 alpha observed in IFN-treated systems in the presence of double-stranded RNA (dsRNA) is indeed caused by an activation of a protein kinase rather than to an inhibition of a phosphoprotein phosphatase by the dsRNA.

Animals↗
PubMed1983

Human interferon and cell growth inhibition. VII. Reversibility of interferon activities.

Interferon (IFN) components isolated from human leukocyte-derived alpha IFN preparations were tested for reversibility of activities in four different human cell lines. As expected, antiviral activity was not reversed by removal of the IFN-containing medium. Growth inhibition by the anticellular component was completely reversible by washing of the cultures, while that of the antiviral component could not be reversed even after careful washing. The results with the components are in agreement with the findings with IFN in the different cell lines. The present study support earlier suggestions that at least two mechanisms of action are involved in growth regulation by IFN in various cell lines.

Antiviral Agents↗
PubMed1984

Detection of hybridomas secreting monoclonal antibodies to human gamma interferon using a rapid screening technique and specificity of certain monoclonal antibodies to gamma interferon.

An immunoprecipitation technique, which uses radiolabeled human gamma interferon (HuIFN-gamma) and a sheep anti-mouse F(ab')2 serum, is described for the rapid detection of mouse monoclonal antibodies to IFN-gamma in hybridoma culture supernatants. This technique which can be performed in 4 h detects both neutralizing and nonneutralizing antibodies to IFN-gamma. Certain monoclonal antibodies prepared against natural (glycosylated) IFN-gamma which neutralized the antiviral activity of natural IFN-gamma bound strongly to rDNA (unglycosylated) IFN-gamma derived from E. coli, but failed to neutralize its antiviral activity.

Animals↗
PubMed1985

Monoclonal antibodies to murine interferon-gamma: affinity purification and molecular characterization of murine interferon-gamma.

Monoclonal antibodies (MAb), AN-18.17.24, obtained by fusing the murine myeloma cell line Ag8.653 with spleen cells from rats immunized with murine interferon gamma (IFN-gamma) produced by the phorbol myristic acetate(PMA)-stimulated T-cell lymphoma L12-R4, were shown to be specific for MuIFN-gamma. An immunoadsorbent column was prepared and used for large-scale purification of MuIFN-gamma produced either by PMA-stimulated L12-R4 cells or by normal T-lymphocytes stimulated with Con A and interleukin 2. The purified product from L12-R4 cells, which retained biologic activity, was made up of two proteins (Mr = 16,500 and 17,500) as determined by sodium dodecyl sulfate gel electrophoresis. By contrast MuIFN-gamma produced by normal T-lymphocytes resulted in two proteins with Mr of 20,600 and 21,800 as determined by sodium dodecyl sulfate gel electrophoresis. These results indicate that MuIFN-gamma produced by L12-R4 tumor cells or by normal T-lymphocytes differ in their molecular weight, probably because of different degrees of glycosylation of the same molecule.

Animals↗
PubMed1985

Increased nuclease sensitivity of the human interferon-alpha 1-related genes and the interferon-beta 1 gene during induction by virus.

The chromatin structure of the human interferon (IFN) genes was evaluated during induction of human lymphoblastoid (Namalwa) cells by Sendai virus. Namalwa cells were treated with bromodeoxyuridine (BrdUrd) for 36-48 h and induced with Sendai virus for 7 h; the nuclear fraction was isolated and treated with low levels of either micrococcal nuclease or DNAse I. DNA was extracted from the nuclease-treated chromatin, restricted with Eco RI and analyzed by Southern blotting using IFN-alpha 1 and -beta 1 cDNA probes. An increase in the digestibility of the IFN-alpha 1-related genes and the IFN-beta 1 gene was observed in chromatin prepared from BrdUrd-treated, Sendai virus-induced Namalwa cells as compared with chromatin from uninduced Namalwa cells. Our results indicate that, during IFN induction in Namalwa cells by Sendai virus, the IFN genes assume a more open conformation consistent with increased transcriptional activity across these genes.

Bromodeoxyuridine↗
PubMed1985

Interferon induction by viruses. XIV. Development of interferon inducibility and its inhibition in chick embryo cells "aged" in vitro.

Studies with a number of viruses revealed a time-dependent acquisition of interferon (IFN) inducibility in primary chick embryo cells as they "aged" in vitro for 2-12 days at a confluent cell density without a medium change. The time-course for the development of IFN inducibility was established by generating and analyzing a family of dose (multiplicity)-response (IFN yield) curves, using Newcastle disease virus (NDV, strain LaSota) as the inducer. Cells produced little or no IFN for the first 4-5 days. Between 5 and 6 days the cells gradually developed the capacity to respond to NDV (and other viruses). Maximal yields of IFN were inducible by day 10. This time-dependent development of IFN inducibility was abrogated almost completely when "aging" was carried out in the presence of drugs that inhibited the synthesis of cyclic derivatives of C20 oxygenated unsaturated fatty acids, i.e., inhibitors of prostaglandin/leukotriene synthesis and the arachidonic acid cascade. Of the prostaglandin synthesis inhibitors, indomethacin was particularly effective. Cells treated on day 0 with 10 micrograms/ml of indomethacin produced 100- to 1000-fold less IFN than controls when induced on day 8. To prevent maximally the development of IFN inducibility, indomethacin must be added within the first 2 days of seeding. After about 2 days, the cells begin to escape the action of the drug. Indomethacin added at the time of induction had no effect on the yield of IFN. IFN inducibility was partially restored when indomethacin was removed during the aging process. "Aging" chick cells in low concentrations of cycloheximide (0.5 micrograms/ml) produced results comparable to incubation with indomethacin. Neither reagent had any marked effect on the rate of total protein or RNA synthesis, nor did their action prevent the induction of stress (heat shock) proteins. Cells "aged" in indomethacin were threefold less efficient in responding to the action of IFN, whereas aging in cycloheximide had no effect on IFN's action. Plaque formation on drug-treated cells was normal for viruses that were poor inducers of IFN. However, both the plaquing efficiency and plaque size of Sindbis virus (an excellent IFN inducer) were enhanced markedly on cells treated with indomethacin or low concentrations of cycloheximide during the aging process. These data implicate a family of fatty acid derivatives of arachadonic acid, including prostaglandins and leukotrienes, in the development of IFN inducibility in primary chick embryo cells "aged" in vitro.

Animals↗
PubMed1986

Induction of xanthine oxidase and heme oxygenase and depression of liver drug metabolism by interferon: a study with different recombinant interferons.

Induction of xanthine oxidase in mouse liver by interferon (IFN) was studied with three different recombinant human leukocyte IFN molecules: IFLrA, IFLrD and the hybrid IFLrA/D(Bgl II). The ability of different IFN species to induce xanthine oxidase correlated with their ability to depress liver cytochrome P-450-dependent drug metabolism, supporting the hypothesis that reactive oxygen metabolites generated by xanthine oxidase might be responsible for this impairment of liver function by IFN. The antioxidant N-acetylcysteine protected in vivo against the depression of liver drug metabolism by IFLrA/D. IFLrA/D was also found to induce liver microsomal heme oxygenase, an effect that was probably secondary to the observed depression of cytochrome P-450.

Animals↗
PubMed1986

Interferon-induced phenotypic changes in human tumor cells relative to the effects of interferon on c-ras oncogene expression.

Three human tumor cell lines derived from an osteosarcoma (OHA cells), a bladder carcinoma (EJ cells), and a gastric sarcoma (SHAC cells) were passaged serially in the presence of human interferon-alpha (IFN-alpha) for extended periods of time. The long-term IFN-alpha treatment induced a partial reversion of OHA tumor cell phenotype as exemplified by inhibition of cell proliferation, lack of cellular overlapping in confluent cultures and marked reduction in tumorigenicity. In contrast, under the same conditions, long-term IFN treatment did not reverse but even potentiated some of the phenotypic characteristics (including tumorigenicity) of EJ and SHAC cells. In the three tumor cell lines, the transforming ability, genomic level, or expression of activated oncogenes, c-Ki-ras, c-Ha-ras, and N-ras, respectively, were unaltered with long-term IFN-alpha treatment. Our data indicate that IFN-induced phenotypic changes are not necessarily associated with changes in oncogene expression.

Cell Differentiation↗