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PubMed1987

Interferon induction by viruses. XV. Biological characteristics of interferon induction-suppressing particles of vesicular stomatitis virus.

A single interferon (IFN) induction-suppressing particle (ISP) of vesicular stomatitis virus (VSV) blocked completely the yield of IFN in a cell otherwise programmed to produce IFN. With mouse L cells as hosts, one lethal hit of UV radiation (D37 = 52.5 ergs/mm2) to the VSV genome sufficed to inactivate ISP activity; however, with "aged" primary chick embryo cells as hosts, it took 198 lethal hits (D37 = 10,395 ergs/mm2). ISP expression in chick cells did not require virus replication or amplified RNA synthesis, but did involve functional virion-associated L protein. ISP in chick cells also were capable of inhibiting, in a multiplicity-dependent manner, the plaquing efficiency of two viruses that require cellular polymerase II (pol II) for replication, e.g., pseudorabies and influenza. The refractory state to IFN inducibility that resulted from infection of chick cells with ISP (VSV tsO5 [UV = 100 hits]) was still extant after 6 days. In contrast, the plaquing efficiency of pseudorabies virus returned to control levels by 5 h after ISP infection. Chick cells infected with UV ISP remained viable, served as hosts for the replication of other viruses, and could be subcultured. Models are presented to account for these contrasting effects. The involvement of viral plus-strand leader RNA as an inhibitor of cellular pol II-dependent RNA synthesis, and the multifunctional activities of the virion-associated L protein, are discussed as possible molecules involved in the action of ISP in chick cells.

Animals↗

PubMed1988

Structure-function analysis of murine interferon-alpha: antiviral properties of novel hybrid interferons.

As described earlier the protein products of the murine interferon (IFN) genes MuIFN-alpha 1, -alpha 2, and -alpha 4 differ in their antiviral activity on hamster (CHO) and mouse (L929) cells. For structure-function analysis, hybrids were prepared between the three genes using common restriction enzyme sites. Natural and hybrid genes were transiently expressed in monkey COS cells. Under the conditions used IFN constituted 20-30% of the total amount of secreted proteins. Using a panel of hybrids either between alpha 1 and alpha 2 or between alpha 1, alpha 2, and alpha 4, the amino-terminal region of the protein, from amino acids 10 to 58, was found to determine its antiviral activity on hamster cells. On mouse cells, the antiviral activities of hybrids between alpha 4 and either alpha 1 or alpha 2 were compared. The high activity of alpha 4 (five to ten times that of alpha 1 or alpha 2) was not transmitted to hybrids having the amino-terminal part of alpha 4, but coincided with the presence of the alpha 4 carboxy-terminal region in all but one hybrid construct. The deletion of five amino acids (positions 103-107) located in this region of alpha 4 did not affect antiviral activity when introduced into MuIFN-alpha 2 and a MuIFN-alpha 42 hybrid by site-directed mutagenesis.

Animals↗

PubMed1988

Cell cycle regulation (G1) by autocrine interferon and dissociation between autocrine interferon and 2',5'-oligoadenylate synthetase expression.

In tertiary MEF undergoing cell cycle progression, autocrine interferon (IFN) is released and constitutive levels of 2',5'-oligoadenylate (2-5A) synthetase activity, low through the cell cycle, surge into a peak within S phase. Treatment of MEF with the autocrine IFN they produce elicits a 2-5A synthetase response from cells positioned in G0 but not from cells in G1 and from cells in S phase. Neutralization of the autocrine IFN by antibody shortens the length of G1 leaving unaltered the kinetics of progression through S and G2 and has no effect on the S phase-linked expression of 2-5A synthetase activity. The growth controlling effect of the autocrine IFN has been mapped to the second part of G1.

2',5'-Oligoadenylate Synthetase↗

PubMed1988

Interferon production in leukocytes of spotted sousliks--effect of hibernation on the interferon response in vitro.

A comparative study of interferon (IFN) production (types alpha and gamma) was carried out using leukocytes from blood, spleen, and peritoneal cavity of sousliks (ground squirrels) active in summer, hibernating in winter, awakened from hibernation in winter, and hibernating in summer. Newcastle disease virus, Radom velogenic strain (NDV-R), and lipopolysaccharide from Escherichia coli (LPS) were used as inducers for IFN-alpha and phytohemagglutinin M (PHA) and concanavalin A (ConA) for IFN-gamma production. There were significant differences between the titers of IFN-alpha and IFN-gamma produced by leukocytes from sousliks hibernating in winter and in summer in comparison with titers of IFNs produced by cells of sousliks active in summer. Cells of hibernating spotted sousliks exhibited diminished IFN production. The IFN production in blood and peritoneal leukocytes of sousliks awakened from winter hibernation was also lower than that observed in cultures of leukocytes of sousliks active in summer, and higher when spleen leukocytes of sousliks awakened from hibernation were examined.

Animals↗

PubMed1989

Interferon induction by viruses. XVIII. Vesicular stomatitis virus-New Jersey: a single infectious particle can both induce and suppress interferon production.

In contrast to wild-type vesicular stomatitis virus (VSV) of Indiana (Ind.) origin which express interferon (IFN) inducing- and IFN induction-suppressing activities as mutually exclusive properties, individual particles of wild-type VSV of the New Jersey (N.J.) serotype (Hazelhurst [H] isolate) paradoxically can both induce IFN and suppress its induction in cells coinfected with a potent inducer of IFN. The properties of IFN induction, and its suppression, appear to reside in the particle that manifests infectivity. Analyses of IFN induction dose-response curves to measure IFN-inducing particles (IFP), and IFN yield-reduction curves to measure IFN induction-suppressing particles (ISP) generated by VSV-N.J.(H) in aged chick embryo cells revealed that (i) a single particle per cell sufficed to induce a quantum (full) yield of IFN, or to suppress fully IFN production by a coinfecting inducing virus, and (ii) the addition of one or more IFP per cell did not suppress the yield of IFN beyond the plateau level. The time-course of IFN production in chick cells infected with VSV-N.J. (H) revealed about a 4-h lag, even when the cells were coinfected with a potent inducer that normally induced IFN 1 or 2 h sooner. Thus, VSV-N.J.(H) appears to regulate the production of IFN in cells--even that initiated by other inducers. Expression of IFP and ISP activities both required primary transcription, with respective genomic targets similar to those reported for VSV-Ind. N.J.(H) is the first wild-type VSV observed to express IFP and ISP activities concomitantly. A model is presented to suggest how these two antagonistic properties might be expressed by a single infectious particle.

Animals↗

PubMed1990

Interferon induction by viruses. XX. Acid-labile interferon accounts for the antiviral effect induced by poly(rI).poly(rC) in primary chick embryo cells.

Primary chick embryo cells which were "aged" in vitro and exposed to poly(rI).poly(rC) developed a disproportionately high degree of resistance to virus challenge in relation to the amount of conventional acid-stable interferon (IFN) produced. Cells were often highly resistant after exposure to a few nanograms of poly(rI).poly(rC) which gave rise to little or no acid-stable IFN. Study of the mechanism(s) responsible showed that this antiviral state was not due to the double-stranded ribonuclease induced in parallel, nor to residual poly(rI).poly(rC) (which this ribonuclease destroyed), but to the production of a hitherto undescribed acid-labile chicken IFN.

Acids↗

PubMed1990

Interferon-alpha modulates the plasma membrane-cytoskeletal complex of human lymphoblastoid cells sensitive to the antiproliferative action of interferon-alpha.

Interferon (IFN)-induced structural changes in the plasma membrane-cytoskeletal complex were investigated in human lymphoblastoid cell lines that differed in sensitivity to the antiproliferative action of IFN-alpha. These cell lines have structurally indistinguishable high-affinity IFN-alpha receptors. By using electron spin resonance techniques, we determined the effect of IFN-alpha on fluidity of the plasma membrane lipid bilayer. By using the ability of cells to redistribute fluorescent anti-immunoglobulin (Ig) into caps at the cell surface, we investigated the effect of IFN-alpha on the mobility of the cell surface. IFN-alpha decreases the fluidity of the plasma membrane lipid bilayer of lymphoblastoid cells sensitive to the antiproliferative action of IFN-alpha. Similarly, IFN-alpha inhibits the anti-Ig-induced redistribution of surface immunoglobulins (capping) of IFN-sensitive cells. These effects of IFN-alpha occur within the first few hours after IFN-alpha addition to cells. However, IFN-alpha had no effect on membrane fluidity or anti-Ig-induced capping of lymphoblastoid cells resistant to the antiproliferative action of IFN-alpha.

Cell Division↗

PubMed1991

Universal antibodies to human interferon-alpha subtypes--the production of antipeptide antibodies to conserved regions of interferon-alpha.

Antibodies to three conserved regions of all human interferon (IFN)-alpha 1 subtypes were raised by immunizing rabbits with short synthetic peptides coupled to a carrier. These peptides correspond to amino acid residues 29-36, 31-36, 126-131, 139-151, and 142-151 of the consensus sequence of IFN-alpha 1. The antibodies were tested for reactivity with IFN-alpha 1, -alpha 2a, -alpha 2b, -alpha 4a, and -alpha 14 and IFN-beta. Most antipeptide antibodies react only weakly with IFN-alpha subtypes; only the antibodies raised against the peptide corresponding to residues 142-151 conjugated to keyhole limpet hemocyanin using glutaraldehyde react appreciably with all IFN-alpha subtypes tested. These antipeptide antibodies are potentially universal antibodies to the human IFN-alpha 1 subtypes, since they exhibit similar binding affinity to all the IFN-alpha subtypes tested and do not react with IFN-beta.

Amino Acid Sequence↗

PubMed1991

Application of four anti-human interferon-alpha monoclonal antibodies for immunoassay and comparative analysis of natural interferon-alpha mixtures.

Four different mouse monoclonal antibodies to human interferon-alpha (IFN-alpha) were evaluated for application in quantitative and comparative analysis of natural IFN-alpha mixtures. Binding to IFN-alpha subtypes in solution revealed individual reactivity patterns. These patterns changed if the IFN-alpha molecules were immobilized either passively to a surface or bound by another antibody. Also, substitution of a single amino acid in IFN-alpha 2 affected the binding, apparently by altering the conformation. Isoelectric focusing of three natural IFN-alpha preparations from different sources, followed by immunoblotting, resulted in individual patterns with each of the four mAbs and also demonstrated variation in the composition of the IFN-alpha preparations. None of the mAbs was subtype specific, but by combining the different mAbs, and also applying polyclonal anti-human IFN-alpha antibodies, it was possible to design sensitive sandwich ELISAs with broad or more limited IFN-alpha subtype specificity.

Adsorption↗

PubMed1992

Interferon pretreatment regulates interferon and interleukin-6 production in L929 cells in a coordinated manner.

Two sublines of L929 cells with different interferon (IFN)-producing capacities synthesized IFN and interleukin-6 (IL-6) simultaneously in response to Sendai virus infection. IFN pretreatment primed the production of both cytokines. However, the difference in IL-6 production between the "high and low producer" L-cell sublines was about one magnitude of order larger than in the case of their IFN production. The determination of the corresponding mRNA levels also reflected this difference.

Animals↗

PubMed1992

Interferon induction by viruses. XXI. Vesicular stomatitis virus: interferon inducibility as a phylogenetic marker.

Forty-five vesiculovirus isolates were systematically compared for their capacity to induce interferon (IFN) in chick embryo cells under conditions such that the maximum (quantum) yield of IFN per cell and the titer of IFN-inducing particles (IFP) could validly be determined. Twelve isolates of the New Jersey (NJ) serotype of vesicular stomatitis virus (VSV) were good inducers, yielding amounts of IFN that ranged in a continuum from 300 to more than 8,000 units per 10(7) cells. These must reflect genetic differences between the closely related viruses. These differences were not reflected in the nucleotide sequence of the viral 3' leader RNA, for analysis of eight of the NJ isolates showed no correlation with the IFN yields. As found in previous smaller surveys, 28 out of 32 VSV isolates of the Indiana (IN) serotype produced little or no IFN, or even suppressed its induction. However, four exceptional IN strains were isolated during 1984 and 1985 from cattle within a relatively circumscribed geographical area in Costa Rica and Panama; all belonged to Indiana virus, type 1, subtype IV, in the proposed G-protein gene evolutionary tree. This is the first example of an IFN-inducing phenotype serving as a phylogenetic marker.

Animals↗

PubMed1992

A method for the assay of "difficult" interferons exemplified with recombinant equine interferon-beta 1.

We wished to assay recombinant equine interferon-beta 1 (rEqIFN-beta 1) but could not obtain satisfactory results with previously described methods. Therefore, we developed a yield-reduction assay, using primary horse peripheral blood mononuclear cells (PBMC) with vesicular stomatitis virus (VSV) for challenge, which proved consistently satisfactory and highly sensitive. It is suggested that this method of assay may be useful for IFNs from other animals where problems are encountered.

Animals↗

PubMed1992

Role of endogenous interferon in the high sensitivity of C3H/10T1/2 cells to the antiviral activity of interferon.

Addition of anti-mouse interferon (IFN) serum to untransformed 10T1/2 cells at the time of virus challenge led to a reduction of the IFN titers as determined by inhibition of CPE. The titers were reduced to values comparable to those usually observed for transformed 10T1/2 cells. In contrast, no change in IFN titers was observed when anti-IFN serum was added to transformed 10T1/2 cells. There was no significant difference between the two types of cells in the level of IFN induced by the challenge virus, VSV. The IFN level was low and did not increase after pretreatment of the cells with IFN. The distinct effect exerted by anti-IFN serum on untransformed and x-ray transformed 10T1/2 cells was not unique and comparable results were obtained in several other normal and transformed cells.

Animals↗

PubMed1992

Cell cycle regulation (G1) by autocrine interferon and dissociation between autocrine interferon and 2',5'-oligoadenylate synthetase expression.

2',5'-Oligoadenylate Synthetase↗

PubMed1993

Reversal of an interferon-gamma-resistant phenotype by poly(I:C): possible role of double-stranded RNA-activated kinase in interferon-gamma signaling.

Indoleamine 2,3-dioxygenase (IDO) is induced in neoplastic cell lines by interferon-gamma (IFN-gamma) treatment. In ME180 cervical carcinoma cells, there is a rapid increase in IDO mRNA accumulation beginning at 4 h after IFN-gamma treatment and continuing for at least 24 h. The IFN-gamma-resistant mutant of ME180, IR3B6B, expresses very low levels of IDO message after IFN-gamma treatment. However, pretreatment of this mutant with poly(I:C) restores normal levels of IDO mRNAs and IDO enzyme activity. Poly(I:C) mediated reversal of the IFN-gamma-resistant phenotype and induction of IDO mRNA are inhibited by 2-aminopurine. In vitro phosphorylation of calf thymus histone using the immunoprecipitated p68 kinase prepared from IFN-gamma-treated ME180 and IR3B6B cells revealed the deficiency of activation of this kinase in IR3B6B cells after IFN-gamma treatment, and treatment of this mutant cells with poly(I:C) restores p68 kinase activity. From these results, we conclude that a double-stranded RNA-dependent kinase is activated by IFN-gamma treatment and its activation correlates with IFN-gamma-mediated induction of the IDO gene.

Drug Resistance↗

PubMed1994

Postnatal anti-interferon-gamma treatment prevents pancreatic inflammation in transgenic mice with beta-cell expression of interferon-gamma.

beta-Cell-targeted expression of interferon-gamma (IFN-gamma) leads to pancreatitis and immune sensitization to beta-cells. This transgenic model is used to explore the possible role of locally produced IFN-gamma in loss of tolerance to beta-cell-specific antigens in insulin-dependent diabetes mellitus (IDDM). The aim of the present study was to test if postnatal treatment with antibodies against IFN-gamma could inhibit morphological changes in the IFN-gamma transgenic pancreas, even though the transgene is expressed during embryogenesis. Treatment with a monoclonal rat anti-mouse IFN-gamma antibody for 6 weeks, starting from 5 to 7 days of age, completely inhibited IFN-gamma-induced morphological changes in the pancreas, and only a modest inflammatory reaction emerged after prolonged treatment for 12 weeks. The lack of morphological changes may reflect the ability of nonterminally differentiated neonatal pancreatic cells to compensate for transgene-induced pathological alterations occurring in utero prior to the antibody treatment. We conclude that inflammation and altered pancreas morphology in the transgenic mice is the result of the biological actions of IFN-gamma and not by disrupted islet development due to transgene overexpression in the pancreatic beta-cells. Furthermore, our treatment schedule can serve as a model for future intervention studies in the transgenic mice, elaborating the role of IFN-gamma in localized inflammatory reactions, IDDM in particular.

Animals↗

PubMed1994

Interferon-alpha 2 produced by normal human leukocytes is predominantly interferon-alpha 2b.

Peripheral blood leukocytes, isolated from the buffy coats of greater than 10,700 normal healthy donors, were induced with Sendai virus to produce biologically active interferon alpha (IFN-alpha). The IFN-alpha was purified to near homogeneity by immunoaffinity chromatography, followed by size-exclusion chromatography. The resultant product, IFN-alpha n3, is reproducibly > or = 98% pure (to be reported elsewhere). The different IFN-alpha proteins in IFN-alpha n3 were separated by reverse-phase high performance liquid chromatography (RP-HPLC) and the identity of the IFN-alpha 2 isolated by HPLC was determined by amino-terminal sequencing. IFN-alpha 2 was found to migrate as two closely eluting peaks on RP-HPLC, and they have been designated as peaks 1.1 and 1.2. Distinction among the three possible variants of IFN-alpha 2, i.e., IFN-alpha 2a, IFN-alpha 2b, and IFN-alpha 2c, was determined by amino-terminal sequencing of the first 35 amino acids in peaks 1.1 and 1.2. Protein sequence data showed that the discriminating amino acids found at positions 23 and 34 are Arg and His, respectively. The presence of Arg and not Lys at amino acid position 23 and His at amino acid position 34 argues that IFN-alpha 2b is the major component in the Sendai virus-induced leukocyte IFN-alpha 2 and that IFN-alpha 2a is not present. These findings were verified by subjecting RP-HPLC peaks 1.1 and 1.2 to CNBr cleavage, followed by separation of the fragments by RP-HPLC and sequencing.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1995

Interferon regulatory factor element and interferon regulatory factor 1 in the induction of major histocompatibility complex class I genes in neural cells.

The role of the MHC-IRF-E and interferon regulatory factor 1 (IRF-1) in the regulation of MHC class I genes in astrocytes was analyzed. Transcriptional activation of MHC class I genes after treatment of astrocytes with various inducers occurred over a period of hours and correlated with cell surface expression. Functional analysis of the MHC class I gene promoter region confirmed that induction was controlled by a restricted region of 88 base pairs containing two well-defined inducible enhancers, the MHC-CRE and the MHC-IRF-E. Further analysis showed that potential MHC-CRE enhancer activity was silent. Therefore, the MHC-IRF-E, rather than the MHC-CRE, appeared responsible for enhancement of the MHC class I gene and was supported by three findings: (1) site-directed mutation of the MHC-IRF-E-abrogated induction, (2) promoter constructs containing IRF-Es as the sole enhancers were highly inducible in astrocytes, and (3) the expression of transcription factor IRF-1, which acts through the MHC-IRF-E to induce MHC class I genes, was induced to high levels in parallel with that of MHC class I induction. The induction of the IRF-1 gene correlated with the prior induction of the gamma-activated factor (GAF) or NF-kappa B, depending on the inducer, indicating that both gamma activation sites (GAS) and kappa B sites in the IRF-1 promoter are important.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗