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PubMed1978

Quantitative determination of human leukocyte interferon by microfluorometric immunoassay with FITC-labeled anti-interferon immunoglobulin.

The possibility of quantitative determination of human leukocyte interferon using FITC-labeled anti-interferon antibody was studied. Anti-interferon immunoglobulin of high specific activity was obtained as a result of long-term immunization of a donkey with human leukocyte interferon preparation and subsequent fractionation and immunoadsorption steps. This immunoglobulin was labeled with FITC and then used for titration of human leukocyte interferon by the fluorescence inhibition immunoassay. The titres of different preparations of human leukocyte interferon in the immunoassay were comparable with the titres of the same preparations detected by the inhibition of a cytopathic effect of VSV.

Animals↗

PubMed1978

Murine interferon system regulation: isolation and characterization of a mutant 3T6 cell engaged in the semiconstitutive synthesis of interferon.

We describe the isolation and characterization of a virus-resistant mutant of murine 3T6 cells. The mutant, designated 3T6-VrB2, displays a high degree of resistance to infection by members of the toga-, rhabdo- and picornavirus classes. The level of this resistance to infection is similar to the parent 3T6 pretreated with approximately 100 lU/ml of interferon. Upon co-cultivation of 3T6-VrB2 cells with interferon-sensitive mouse cells, an antiviral state is induced in the latter cells as measured by a reduction of virus yield following infection. The nature of the induction is defined by a series of experiments using anti-mouse interferon antiserum. In the presence of this antiserum, the ability of the mutant to induce an antiviral state in interferon-sensitive mouse cells upon co-cultivation is eliminated. Additionally, growth of the mutant cells in the presence of this antiserum causes a reversal of the virus-resistant phenotype. Our results indicate that 3T6-VrB2 contains a mutation affecting the regulation of the murine interferon system such that the cell is engaged in the semiconstitutive synthesis of interferon.

Cell Line↗

PubMed1975

Interferon action II. Membrane-bound alkaline ribonuclease activity in chick embryo cells manifesting interferon-mediated interference.

Membrane fractions from chick embryo cells manifesting viral interference mediated by interferon or poly(I)-poly(C) contain high levels of an alkaline ribonuclease. Enhanced RNase activity is not observed when inhibitors of cell protein or RNA synthesis are present during interferon treatment, or when heterologous interferon is used. The RNase associated with comparable membrane fractions from cells treated with mock-interferon is about 1/10 as active, and shows qualitative differences. In principle, divergent views of interferon action may be reconciled to a common mode of action by postulating that viral interference results from a newly induced or activated RNase of cellular origin and proper specificity that acts to reduce the accumulation and functional capacity of newly synthesized viral RNAs, particularly mRNA. Previous data in support of interferon's acting to inhibit virion-derived transcription in vivo are now interpreted as demonstrating enhanced degradation of viral transcripts (mRNA).

Animals↗

PubMed1979

Interferon action: induction of specific proteins in mouse and human cells by homologous interferons.

Treatment of mouse (Ehrlich ascites tumor and L929) and human (FS4, GM258, etc.) cells with homologous interferons results in the induction of several proteins. Extracts obtained from cells labeled with [35S]methionine in the absence or presence of interferon were fractionated on poly(I) . poly(C)-agarose columns. The proteins retained on the columns revealed, upon sodium dodecyl sulfate/polyacrylamide gel electrophoresis, three protein bands in mouse cells (Mr 120,000; 80,000; and 67,000) and two in human cells (Mr 120,000 and 80,000) which were detected in the extracts of interferon-treated but not of untreated cells. These proteins were retained on double-stranded RNA [poly(I) . poly(C)-agarose] columns but very poorly, if at all, on single-stranded RNA [poly(I)- or poly(C)-agarose] columns, suggesting that they have an affinity for double-stranded RNA. In addition, interferon treatment of human fibroblasts greatly increased the labeling of three other protein bands (Mr 88,000; 67,000; and 56,000) which were detected in whole extracts but were not appreciably retained on poly(I) . poly(C)-agarose columns. The appearance of the induced proteins was blocked by actinomycin D if added together with interferon, indicating that transcription of certain genetic information is required. The possible correlation between the induced proteins described here and the elevated levels of certain enzymes in interferon-treated cells (a protein kinase and 2'-5'-oligoadenylate synthetase) is at present unclear.

Animals↗

PubMed1992

Interferon action: nucleolar and nucleoplasmic localization of the interferon-inducible 72-kD protein that is encoded by the Ifi 204 gene from the gene 200 cluster.

The interferons are cytokines with antiviral, cell growth regulatory, and immunomodulatory activities. These activities are mediated by the proteins induced by the interferons. Earlier we described a gene cluster (the 200 cluster) consisting of at least six adjacent, interferon-activatable genes located next to the erythroid alpha-spectrin locus on murine chromosome 1. The genes of the cluster arose by repeated gene duplication and they specify proteins with pronounced sequence similarity. We have now raised polyclonal antibodies against a segment from one of these proteins (the 204 protein of 72 kD). Using these, we established that the 204 protein is a phosphoprotein whose level in cells from various murine lines can be increased up to 75-fold upon treatment with alpha interferon. Experiments involving fractionation of cell lysates and indirect immunofluorescence microscopy of control and interferon-treated cells revealed that the 204 protein is nucleolar and nucleoplasmic. This conclusion was confirmed by co-localization with B23, a known nucleolar protein. The 204 protein is the first interferon-induced protein found to be located in the nucleoli, the subcellular organelles of ribosomal RNA production and ribosome assembly. It remains to be seen whether the 204 protein affects any of these processes. Studies on 204 protein function should be facilitated by the availability of complete cDNA clones and the finding of cell lines in which the expression of this protein is impaired.

Amino Acid Sequence↗

PubMed1979

Interferon induction with Newcastle disease virus in FS-4 cells: effect of priming with interferon and of virus inactivating treatments.

Inoculation of human FS-4 cells with Newcastle disease virus (NDV) resulted in the induction of two distinct interferon responses, one that peaked at about 5 hr (early response) and one that reached a maximum between 10 to 24 hr after inoculation (second response). The early interferon response was enhanced by previous treatment of the cells with interferon (priming), whereas the second response decreased after interferon treatment in a dose-dependent manner. The early response diminished with decreasing multiplicities of infection, the magnitude of the second response in unprimed cells was relatively independent of the dose of NDV employed. The early interferon response was sensitive to inhibition by actinomycin D for only 1 hr after inoculation. In marked contrast, the second response remained sensitive to inhibition by actinomycin D until 12 hr after inoculation. The ability of NDV to induce the second response was greatly diminished by irradiation of the virus with ultraviolet light or by its treatment with hydroxylamine, whereas the ability to stimulate the early response was relatively resistant to these virus-inactivating treatments. Treatment of NDV with hydroxylamine abolished the virus to induce the second response at the same rate as it destroyed infectivity. The results suggest the existence of at least two distinct mechanisms of interferon induction by NDV; the early response is triggered either by a virion component or by a product of primary transcription, whereas induction of the second response requires the expression of some functions of the virus not needed for triggering the early response.

Animals↗

PubMed1979

Rat interferons. VI. Heterologous interferon in the treatment of viral infections.

In previous studies in vitro we demonstrated the protection of mouse cells against viral infections by rat interferon. In continuation, the present paper reports results of a study designed to confirm this heterospecific activity of rat interferon in vivo. Experiments were carried out with mice of the inbred 129/AoBoy strain, inoculated intranasally or intraperitoneally with EMC-strain Col MM, VSV and influenza A 055/74 viruses, and treated with mouse or rat interferon administered by the same routes as infection. Both interferons exhibited protective action. The therapeutic effect of the mouse and rat interferons was dependent on the infecting dose of the viruses. Rat interferon proved more effective in the treatment of mice infected intraperitoneally than mice infected intranasally.

Animals↗

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

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↗

PubMed1979

Interferon production in the murine mixed lymphocyte culture. I. Interferon production caused by differences in the H-2 K and H-2 D region but not by differences in the I region or the M locus.

Little has been made previously of the observation that interferon is generated in the murine mixed lymphocyte reaction (MLR). We have found high levels of interferon in the supernatants of MLR between spleen cells of mice of different H-2 type after one to two days of culture. Interferon production was also seen in strain combinations that differed only in the K or D region of the H-2 complex. There was no production of interferon in strain combinations differing in the M locus or in the I region of the H-2 complex. The latter combinations are known not to induce cytotoxic effector cells. Thus, there seems to be a dichotomy in allogeneic determinants between those of the I region and of the M locus inducing primarily lymphoproliferation, and those of H-2K and H-2D inducing cytotoxic activity and interferon production.

Animals↗

PubMed1979

Production of interferon in the murine mixed lymphocyte culture. II. Interferon production is a T cell-dependent function, independent of proliferation.

Interferon production occurs after two days of culture in murine mixed lymphocyte cultures (MLC). This was demonstrated in various combinations of mouse spleen cells differing at the major histocompatibility (H-2) locus. Interferon production could be demonstrated in one-way MLC when F1/parent combinations were used and in reactions in which one partner was treated by puromycin. After treatment of both cell populations with mitomycin C, interferon production occurred in the absence of lymphoproliferation. Interferon production in response to alloantigen did not occur in spleen cell cultures of nude mice and in cultures treated by anti-theta antiserum plus complement indicating that interferon production is a T cell-dependent function.

Animals↗

PubMed1978

Role of endogenous interferon in the anti-tumor effect of poly I-C and statolon as demonstrated by the use of anti-mouse interferon serum.

We have determined the effect of sheep anti-mouse interferon globulin on the anti-tumor effects of poly I-C, statolon, tilorone, pyran copolymer and BCG in mice inoculated with Ehrlich ascites or L 1210 lymphoma cells. Whereas the anti-tumor effects of poly I-C and statolon were nulified when mice were injected with immunoglobulins, the anti-tumor effects of pyran copolymer and BCG were not modified by this treatment. We conclude that interferon mediates the anti-tumor activity of poly I-C and statolon in these experimental systems. It is suggested that anti-interferon serum provides a direct method of determining whether other biologic effects attributed to viruses, poly I-C, statolon, tilorone, pyran copolymer (and possibly other interferon inducers) are mediated or not by interferon.

Animals↗

PubMed1992

Three cases of posttransfusion hepatitis C treated with interferon-alpha. Confirmation of a carrier state by detection of hepatitis C virus RNA after interferon therapy.

Interferon therapy is useful for decreasing the serum ALT level and improving liver histology in patients with chronic non-A, non-B hepatitis. This study examined the effect of interferon therapy in acute cases of posttransfusion hepatitis C. We report on three cases in which interferon alpha was administered at 100-220.5 million units. HCV RNA became undetectable during interferon administration and the ALT level declined to the normal range. However, after the cessation of the therapy, the ALT level began to fluctuate and HCV RNA reappeared in two patients. We concluded that interferon therapy for the acute phase of posttransfusion hepatitis is useful for suppressing viral replication and quickly improving the ALT level, but it can not always prevent the development of chronic hepatitis. Furthermore, there was a close correlation between the profile of HCV RNA and that of the ALT level, indicating that the replication of HCV plays an important role in liver injury.

Adult↗

PubMed1992

Inhibition of lymphocyte proliferation by bovine trophoblast protein-1 (type I trophoblast interferon) and bovine interferon-alpha I1.

Bovine trophoblast protein-1 (bTP-1) is a Type I interferon secreted by the bovine trophoblast from about Day 15 of pregnancy. It is not known whether bTP-1 has functional properties in common with other interferons. The aim of the present study was to determine whether bTP-1 inhibits proliferation of lymphocytes induced by mitogens, mixed lymphocyte cultures (MLC) and interleukin-2 (IL-2) and, if so, whether this activity is similar to that of a related interferon, bovine interferon-alpha I1 (bIFN-alpha I1). Stimulation of lymphocyte proliferation caused by phytohemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM) was inhibited by bTP-1 and bIFN-alpha I1 without any reduction in cell viability. Maximum or near-maximum inhibition (less than 50%) was achieved at concentrations of 0.5-5.0 nM of bTP-1 and bIFN-alpha I1. Cells stimulated with PWM were less inhibited than cells stimulated with PHA and Con A. Both bTP-1 and bIFN-alpha I1 inhibited MLC to a greater degree than lectin-stimulated cells (maximum inhibition was 78% or greater). Also, bTP-1 and bIFN-alpha I1 slightly inhibited incorporation of [3H]thymidine ([3H]TdR) induced by the combination of phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), and calcium ionophore A23187. Finally, bTP-1 and bIFN-alpha I1 had bimodal effects on incorporation of [3H]TdR by IL-2-induced lymphocytes. Incorporation of [3H]TdR was increased at 0.005 nM and 0.05 nM concentrations while higher concentrations caused a slight decrease in [3H]TdR incorporation. Results confirm that bTP-1 inhibits lymphocyte proliferation in a manner similar to that caused by the leukocyte-derived interferon, bIFN-alpha I1. Incomplete inhibition of mitogen-induced proliferation and differences in degree of inhibition between various stimulators suggest that bTP-1 and bIFN-alpha I1 preferentially inhibit certain lymphocyte subpopulations. Local inhibition of lymphocyte proliferation caused by bTP-1 may help protect the allogeneic conceptus from immune responses to fetal antigens or regulate the release of cytokines from endometrial lymphocytes.

Animals↗

PubMed1975

Interferon activity produced by translation of human interferon messenger RNA in cell-free ribosomal systems and in Xenopus oöcytes.

Translation of messenger RNA isolated from poly(rI)-poly(rC)-induced human fibroblasts in cell-free ribosomal systems and in Xenopus oocytes resulted in the production of biologically active proteins that had the properties of human fibroblast interferon. The translation in the oocytes was much more efficient, giving approximately 500 times higher titers of interferon activity than the cell-free systems. A control messenger RNA isolated from noninduced human fibroblasts, did not code for interferon synthesis in these systems. Both messenger RNA preparations stimulated [3H]amino-acid incorporation into trichloroacetic acid-insoluble material. The radioactive products and their immunoprecipitates were electrophoresed on polyacrylamide gels under denaturing conditions. The products resulting from the translation of the control (uninduced) messenger RNA in oocytes contained a major protein of approximately 45,000 molecular weight. The messenger RNA isolated from poly(rI)-poly(rC)-induced cells stimulated the synthesis of an additional 25,000 molecular weight protein that electrophoresed in the same position as human fibroblast interferon. These results suggest that human fibroblast interferon was synthesized by the translation of its messenger RNA in Xenopus oocytes and in cell-free ribosomal systems.

Animals↗

PubMed1976

Differential sensitivity of herpes simplex virus types 1 and 2 to human interferon: antiviral effects of interferon plus 9-beta-D-arabinofuranosyladenine.

With use of a standard assay for antiviral compounds, in which the compound to be tested is added after absorption of virus, the minimal inhibitory concentration (MIC) of human interferon for several strain of herpes simplex virus type 2 (HSV-2) is five to 10 times greater than it is for two strains of herpes simplex virus type 1 (HSV-1). This differential susceptibility of HSV types to interferon is found whether tests are done with a liquid overlay and microtiter plates or with agarose overlays and appears to be a distinguishing biological marker. When the MIC of interferon is tested by microtiter or agarose methods and interferon is allowed to incubate for 24 hr before virus is added, values for HSV-1 and HSV-2 are similar and much smaller in magnitude. These results support earlier data indicating that adenine arabinoside and interferon are synergistic against herpes simplex virus type 1 in vitro and indicate that these agents are additive but not synergistic against herpes simplex virus type 2.

Antiviral Agents↗

PubMed1975

Distinct molecular species of human interferons: requirements for stabilzation and reactivation of human leukocyte and fibroblast interferons.

Human fibroblast interferon preparations were completely stabilized to 100 degrees C by sodium dodecyl sulphate (SDS) in the presence of mercaptoethanol, but only a minor fraction of their activities were stabilized by SDS without mercaptoethanol. On the contarary, human leukocyte interferon preparations were completely stabilized to 100 degrees C by SDS in the absence of mercaptoethanol, but only a minor fraction of their activities were stabilized by SDS in the presence of mercaptoethanol. Furthermore, human fibroblast interferon preparations whose activities had been destroyed by boiling at 100 degrees C were completely reactivated by SDS under reducing conditions, but only a minor part of their activities were restored by SDS in the absence of reduction. On the contrary, human leukocyte interferon preparations whose activities had been destroyed by boiling at 100 degrees C were completely reactivated by SDS in the absence of reduction, but only a minor part of their activities were restored by SDS under reducing conditions. These data suggest that there are distinct molecular species of human interferons.

Biological Assay↗

PubMed1976

Purification of two components of mouse L cell interferon: electrophoretic demonstration of interferon proteins.

Mouse L cell interferon induced by Newcastle disease virus was purified by the procedure described previously (Yamamoto et al. 1974) followed by gel filtration. The two fractions obtained containing interferon species S (36000 daltons) and F (24000 daltons), respectively, were analysed electrophoretically at pH 4-3, or in the presence of sodium dodecyl sulphate (SDS) at pH 7-2. In both fractions, interferon activity was invariably associated with distinct protein bands. In the F-containing fraction there were essentially no other proteins, and in the S-containing fraction, impurity proteins were well separated from the interferon activity. The apparent mol. wt. determined by SDS-gel electrophoresis showed little or no dependence on gel concentration, suggesting that the interferons had low carbohydrate contents, and did not change after reduction with thiol reagents in SDS and urea.

Animals↗