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Mechanism of the Intracellular Killing and Modulation of Antibiotic Susceptibility of Listeria monocytogenes in THP-1 Macrophages Activated by Gamma Interferon

Ouadrhiri, Youssef; Scorneaux, Bernard; Sibille, Yves; Tulkens, Paul M.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/1999 Português
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Listeria monocytogenes, a facultative intracellular pathogen, readily enters cells and multiplies in the cytosol after escaping from phagosomal vacuoles. Macrophages exposed to gamma interferon, one of the main cellular host defenses against Listeria, become nonpermissive for bacterial growth while containing Listeria in the phagosomes. Using the human myelomonocytic cell line THP-1, we show that the combination of l-monomethyl arginine and catalase restores bacterial growth without affecting the phagosomal containment of Listeria. A previous report (B. Scorneaux, Y. Ouadrhiri, G. Anzalone, and P. M. Tulkens, Antimicrob. Agents Chemother. 40:1225–1230, 1996) showed that intracellular Listeria was almost equally sensitive to ampicillin, azithromycin, and sparfloxacin in control cells but became insensitive to ampicillin and more sensitive to azithromycin and sparfloxacin in gamma interferon-treated cells. We show here that these modulations of antibiotic activity are largely counteracted by l-monomethyl arginine and catalase. In parallel, we show that gamma interferon enhances the cellular accumulation of azithromycin and sparfloxacin, an effect which is not reversed by addition of l-monomethyl arginine and catalase and which therefore cannot account for the increased activity of these antibiotics in gamma interferon-treated cells. We conclude that (i) the control exerted by gamma interferon on intracellular multiplication of Listeria in THP-1 macrophages is dependent on the production of nitric oxide and hydrogen peroxide; (ii) intracellular Listeria may become insensitive to ampicillin in macrophages exposed to gamma interferon because the increase in reactive oxygen and nitrogen intermediates already controls bacterial growth; and (iii) azithromycin and still more sparfloxacin cooperate efficiently with gamma interferon...

Microarray Analysis Identifies Interferon-Inducible Genes and Stat-1 as Major Transcriptional Targets of Human Papillomavirus Type 31

Chang, Yijan E.; Laimins, Laimonis A.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/2000 Português
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Human papillomaviruses (HPVs) infect keratinocytes and induce proliferative lesions. In infected cells, viral gene products alter the activities of cellular proteins, such as Rb and p53, resulting in altered cell cycle response. It is likely that HPV gene products also alter expression of cellular genes. In this study we used microarray analysis to examine the global changes in gene expression induced by high-risk HPV type 31 (HPV31). Among 7,075 known genes and ESTs (expressed sequence tags) tested, we found that 178 were upregulated and 150 were downregulated twofold or more in HPV31 cells compared to normal human keratinocytes. While no specific pattern could be deduced from the list of genes that were upregulated, downregulated genes could be classified to three groups: genes that are involved in the regulation of cell growth, genes that are specifically expressed in keratinocytes, and genes whose expression is increased in response to interferon stimulation. The basal level of expression of several interferon-responsive genes was found to be downregulated in HPV31 cells by both microarray analysis and Northern blot analysis in different HPV31 cell lines. When cells were treated with alpha or gamma interferon, expression of interferon-inducible genes was impaired. At high doses of interferon...

Frequencies of Virus-Specific CD4+ and CD8+ T Lymphocytes Secreting Gamma Interferon after Acute Natural Rotavirus Infection in Children and Adults

Jaimes, María C.; Rojas, Olga Lucía; González, Ana María; Cajiao, Isabela; Charpilienne, Annie; Pothier, Pierre; Kohli, Evelyne; Greenberg, Harry B.; Franco, Manuel A.; Angel, Juana
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/2002 Português
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Human rotavirus-specific CD4+ and CD8+ T-cell responses in peripheral blood lymphocytes were studied using a flow cytometric assay that detects the intracellular accumulation of cytokines after short-term in vitro antigen stimulation. The frequencies of virus-specific T cells that secrete gamma interferon and interleukin-13 (IL-13) were determined in adults and children during the acute or convalescent phase of rotavirus-induced diarrhea, in asymptomatically infected adults and laboratory workers who worked with human stool samples containing rotavirus, and in healthy adults. Significantly higher frequencies of rotavirus-specific interferon gamma-secreting CD8+ and CD4+ T cells, but not IL-13-secreting T cells, were detected in symptomatically infected adults and exposed laboratory workers than in healthy adults and children with acute rotavirus diarrhea. The levels of rotavirus-specific T cells returned to levels found in healthy adults by 32 days after the onset of rotavirus diarrhea in most adult subjects. Children with rotavirus diarrhea had undetectable or very low levels of CD4+ and CD8+ T cells that secrete gamma interferon. Adult cytomegalovirus-seropositive individuals had frequencies of cytomegalovirus-specific T cells that secrete gamma interferon that were approximately 20 times the level of rotavirus-specific T cells. This result suggests that rotavirus is a relatively poor inducer of circulating memory T cells that secrete gamma interferon. The frequencies of gamma interferon-secreting CD4+ and CD8+ T cells and the frequencies of IL-13-secreting CD4+ T cells responding to the T-cell superantigen staphylococcal enterotoxin B (SEB) were lower in children than in adults. In both adults and children...

Duration of effect of interferon aerosol prophylaxis of vesicular stomatitis virus infection in mice.

Wyde, P R; Sun, C S; Wilson, S Z; Knight, V
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1985 Português
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Mice were exposed for 8 h to continuous small-particle aerosols containing natural mouse alpha interferon (estimated dosage 100 U per mouse) or one of two concentrations of hybrid recombinant alpha interferon A/D bgl (estimated dosages of 100 and 10,000 U per mouse, respectively). On days 1, 3, 5, 7, and 9 after exposure to these interferons, three mice from each group were inoculated intranasally with 100 PFU of vesicular stomatitis virus. Control mice were exposed to aerosols of saline or inoculated intraperitoneally with either natural mouse alpha interferon (350 U) or one of two doses of hybrid recombinant alpha interferon A/D bgl (350 or 35,000 U) and challenged similarly. Of mice injected intraperitoneally, only those given 35,000 U of hybrid recombinant alpha interferon A/D bgl 24 h before virus challenge were protected from pulmonary infection, compared with the saline-treated control mice. Of mice given 100 U of either interferon by small-particle aerosol, only those exposed 24 h before inoculation of vesicular stomatitis virus had reduced pulmonary titers of the virus. However, of mice given ca. 10,000 U of hybrid recombinant alpha interferon A/D bgl by small-particle aerosol, all groups except those exposed 9 days before virus inoculation had significantly reduced lung virus titers.

Interferon aerosol suppression of vesicular stomatitis virus replication in the lungs of infected mice.

Wyde, P R; Wilson, S Z; Sun, C S; Knight, V
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1984 Português
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Mice were inoculated intranasally with vesicular stomatitis virus 16 to 22 h after being exposed to small-particle aerosols of saline, natural mouse alpha interferon, recombinant human alpha interferon A, or hybrid recombinant human alpha interferon A/D bgl for 2, 4, or 8 h. Compared with comparably inoculated, untreated mice, significantly reduced levels of vesicular stomatitis virus were observed in the lungs of animals treated with any interferon preparation for 8 h and in groups treated with mouse alpha interferon or hybrid recombinant human alpha interferon A/D bgl for 4 h. No significant reductions in lung virus titers were observed in any group treated with interferon for 2 h or in any of the groups treated with saline.

Interferon production by a human lymphoblastoid cell line (DG-75) free of the Epstein-Barr genome.

Lazar, A; Reuveny, S; Minai, M; Traub, A; Mizrahi, A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1981 Português
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A new lymphoblastoid cell line, DG-75, was investigated for its ability to produce interferon. DG-75 cells, previously shown to be free of Epstein-Barr virus genome and receptors, could be grown in submerged culture and could produce interferon in titers comparable to interferon produced by Namalva cells. The interferon produced was similar in size to the Namalva interferon as determined by gel filtration in Ultrogel AcA54. The DG-75 cells present a new source of large quantities of interferon which may be safer for human use than the Namalva interferon.

Necessity and sufficiency of beta interferon for nitric oxide production in mouse peritoneal macrophages.

Zhang, X; Alley, E W; Russell, S W; Morrison, D C
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1994 Português
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Bacterial lipopolysaccharide and some cytokines can activate macrophages to secrete nitric oxide. Macrophage-derived nitric oxide is a key cytotoxic factor for microbicidal and tumoricidal processes. We report here that a monoclonal antibody specific for beta interferon inhibited lipopolysaccharide-induced nitric oxide production in thioglycolate-elicited C3HeB/FeJ peritoneal macrophages and macrophage-like cell line RAW 264.7. In addition, exogenous added beta interferon enabled lipopolysaccharide-hyporesponsive thioglycolate-elicited C3H/HeJ peritoneal macrophages to produce nitric oxide in response to lipopolysaccharide. These data support the concept that beta interferon provides an essential signal(s) for lipopolysaccharide-triggered nitric oxide production by mouse macrophages. Heat-killed Staphylococcus aureus, a gram-positive bacterium which was unable to initiate nitric oxide production in thioglycolate-elicited C3HeB/FeJ peritoneal macrophages in vitro, promoted nitric oxide formation in the presence of beta interferon, suggesting that beta interferon may be a general cofactor necessary for bacterium-derived stimulus-induced nitric oxide production in these macrophages. However, neither beta interferon nor tumor necrosis factor alpha...

INTERFERON SYNTHESIS IN X-IRRADIATED ANIMALS, IV. DONOR-TYPE SERUM INTERFERONS IN RAT-TO-MOUSE RADIATION CHIMERAS INJECTED WITH NEW CASTLE DISEASE VIRUS*

De Maeyer-Guignard, Jaqueline; De Maeyer, Edward; Jullien, Pierre
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1969 Português
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C3H/He mice were exposed to total-body X-irradiation of 1000 roentgens and received thereafter 107 xenogeneic Wistar rat marrow cells intravenously. In these rat-to-mouse chimeras, serum interferon-producing capacity upon injection of Newcastle disease virus was examined four weeks after grafting. Normal levels of circulating interferon were produced. The interferon, however, had the species specificity of rat interferon, being 20 times more active in rat embryo fibroblasts than in mouse embryo fibroblasts. Moreover, it behaved like rat interferon when filtered on Sephadex G-100 dextran gel, displaying one peak of activity in the 90,000 molecular-weight range and two incompletely separated peaks of 32,000 and 24,000, respectively, in the 30,000 molecular-weight region. The fact that the interferon is of the donor type in rat-to-mouse chimeras permits us to conclude that circulating interferon induced by New-castle disease virus is made in bone-marrow-derived cells.

Effect of human alpha A interferon on influenza virus replication in MDBK cells.

Ransohoff, R M; Maroney, P A; Nayak, D P; Chambers, T M; Nilsen, T W
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1985 Português
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To determine the molecular mechanism whereby interferon induces resistance to influenza virus, we began an investigation of influenza virus replication in MDBK cells treated with recombinant human alpha A interferon. Negative- and positive-strand virus-specific RNA accumulation was monitored by blot hybridization with cloned probes. Primary transcription (transcription of infecting viral negative strands by the virion-associated polymerase) was inhibited by interferon treatment of MDBK cells. At moderate levels of interferon treatment (10 U/ml), this inhibition was restricted to transcripts of polymerase genes, whereas at higher levels of interferon treatment (50 U/ml), accumulation of all primary transcripts was markedly inhibited. Secondary transcripts and viral negative strands did not accumulate to any significant extent in interferon-treated MDBK cells. These results suggest that interferon-induced mechanisms which inhibit influenza virus replication in MDBK cells act at the level of primary transcription.

Interferon response in normal and Aleutian disease virus-infected mink.

Wiedbrauk, D L; Hadlow, W J; Ewalt, L C; Lodmell, D L
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1986 Português
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Studies were done to determine whether differences in interferon production are responsible for the resistance of pastel mink to Aleutian disease. The abilities of normal pastel and sapphire mink to produce interferon when inoculated with either Newcastle disease virus or a synthetic polyribonucleotide, poly (I):poly (C), were identical, even to the production of a novel, acid-labile interferon. The resistance of pastel mink to Aleutian disease did not correlate with interferon production, because neither sapphire nor pastel mink produced detectable amounts of interferon when infected with either the Pullman strain of Aleutian disease virus (ADV) or the highly virulent Utah I strain. Sapphire mink infected with the Pullman strain responded normally to poly (I):poly (C) early in the course of the disease, but interferon production was impaired late, when the mink were hypergammaglobulinemic and had renal, vascular, and hepatic lesions. These data suggest that ADV Pullman neither stimulates nor interferes with interferon production in infected mink and may represent a mechanism whereby ADV can more readily establish infection.

Inverse relationship between constitutive gamma interferon production and human T-cell lymphoma/leukemia virus expression in cultured T lymphocytes.

Moore, J L; Poiesz, B J; Zamkoff, K W; Merl, S A; Hanna, S; Gazdar, A F; Comis, R L
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1985 Português
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Particular interest in human T lymphocyte lymphoma/leukemia virus (HTLV) derives from the close association of HTLV with several types of human mature T lymphocyte malignancies and the strong possibility that HTLV is the causative agent of this group of leukemias and lymphomas. This is the first report to show that HTLV expression in T lymphocytes cultured in vitro is inversely proportional to constitutive gamma interferon production. Of 16 fresh T lymphocyte cultures established from patients with mature T lymphocyte neoplasias, 3 were grown continuously for over 3 years and 13 were grown for 2 to 8 months in culture. Of the 16 cultures, 9 were HTLVp19 positive and interferon negative, whereas the remaining 7 were HTLVp19 negative or weakly positive and also interferon positive (12 to 105 U/ml). The prototype HTLV-positive T-cell line (HUT102) was examined over a long-term culture and after selective cell cloning for high virus yield. Results indicate that early-passage, low-HTLV-producing HUT102 cells constitutively produced significant levels of gamma-immune interferon. In late-passage and cloned HUT102 cells, an increase in HTLV production was concordant with a decrease in constitutive interferon production and the loss of mature T lymphocyte antigens. Transformation of human umbilical cord blood lymphocytes by HTLV was possible only after cocultivation with the non-interferon...

Virus Replication and High-Titered Interferon Production in Human Leukocyte Cultures Inoculated with Newcastle Disease Virus

Wheelock, E. Frederick
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1966 Português
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Wheelock, Frederick E. (Western Reserve University, Cleveland, Ohio). Virus replication and high-titered interferon production in human leukocyte cultures inoculated with Newcastle disease virus. J. Bacteriol. 92:1415–1421. 1966.—High titers of interferon (20,480 culture-protecting units per ml) are produced in freshly prepared human leukocyte cultures inoculated with a Newcastle disease virus (NDV)-cell multiplicity of 1:1. NDV replicates to low titers in these cultures. Incubation of leukocytes at 37 C for 24 hr prior to inoculation of NDV results in almost complete loss of detectable interferon production, but virus replicates to higher titers than in the freshly prepared cultures. In contrast, no diminution of interferon production in response to phytohemagglutinin (PHA) occurs on 24 hr of incubation of cultures prior to addition of PHA. Experiments with cultures of predominantly pure cell fractions of peripheral blood indicate that the lymphocyte fraction produces interferon in response to either NDV or PHA, and that polymorphonuclear leukocytes produce no interferon in response to these agents. These studies suggest a hitherto unsuspected ability of human lymphocytes to produce high titers of interferon in vivo.

High-yield interferon induction by 10-carboxymethyl-9-acridanone in mice and hamsters.

Taylor, J L; Schoenherr, C K; Grossberg, S E
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1980 Português
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10-Carboxymethyl-9-acridanone (CMA) was shown to be a very potent interferon inducer in young and old Swiss albino as well as congenitally asplenic mice. This compound (molecular weight, 275) induced titers of interferon in plasma comparable to those obtained with the best viral inducers, attaining > 400,000 U/ml in mice in 2 to 3 h. CMA concentrations were highest in mouse plasma 1 h after intraperitoneal or oral delivery. Induction was dose dependent over a wide range. Intraperitoneal, subcutaneous, or intramuscular injections of CMA gave comparable ranges of interferon titers. Oral delivery by gavage gave lower titers (65,000 U/ml), but higher than those reported with other low-molecular-weight interferon inducers in mice. CMA injected into week-old hamsters (which usually produce iterferon poorly) induced levels of interferon as high as 6,400 U per ml of plasma in a dose-dependent fashion, but kinetics of interferon induction was less rapid than in mice. The mouse and hamster interferons induced by CMA had physical characteristics similar to those of virus-induced interferons of the homologous species. The unusually high yields of interferon obtainable with this chemical inducer suggest its use for further experimental antiviral or antitumor therapy.

Impaired interferon production and natural killer cell activation in patients with the skin cancer-prone disorder, xeroderma pigmentosum.

Gaspari, A A; Fleisher, T A; Kraemer, K H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1993 Português
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Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder with sun sensitivity, markedly increased skin cancer susceptibility, and defective DNA repair without consistently identified symptoms of immune deficiency. We examined natural killer (NK) cell activity and interferon production in peripheral blood lymphocytes (PBL) of eight XP patients who had multiple primary skin cancers. The XP patients had normal numbers of T cells and NK cells, as well as normal lymphokine-activated killer cell activity and normal tumor necrosis factor-alpha production. Unstimulated NK cell function was 40% of normal controls in five XP patients, but was normal in three other XP patients. However, PBL from all the XP patients tested showed no enhancement of NK activity by the interferon inducer, polyinosinic acid:polycytidilic acid (polyIC) but enhancement by interferon-alpha was normal, suggesting an impairment in interferon production. Parallel studies in non-XP skin cancer patients revealed that both unstimulated and polyIC-enhanced NK activity were normal. Further investigation using PBL from XP patients revealed that the production of interferon-gamma after stimulation with interferon inducers (polyIC, interleukin 2, or K562 tumor cells) was 13-43% of normals. These data indicate that XP lymphocytes have a defect in production of interferons and suggest that defective interferon production...

NF-kappa B-independent activation of beta-interferon expression in mouse F9 embryonal carcinoma cells.

Ellis, M J; Goodbourn, S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 25/10/1994 Português
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We have examined the behaviour of the beta-interferon promoter in mouse F9 embryonal carcinoma cells. In undifferentiated cells, the beta-interferon promoter is not responsive to dsRNA or to Sendai virus. In cells stimulated to differentiate into parietal endoderm by treatment with retinoic acid, the beta-interferon promoter responds to both inducers, but only Sendai virus can activate the transcription factor NF-kappa B previously thought to be essential for beta-interferon induction. Differentiated F9 cells therefore present an unprecedented situation in which induction of the beta-interferon gene does not require NF-kappa B. In addition to these differences, induction by dsRNA, but not by Sendai virus, is significantly enhanced by a pretreatment with interferon (priming). These observations suggest that paramyxo-viruses can participate in beta-interferon induction in a manner that is distinct from a simple generator of dsRNA. Analysis of the promoter requirements for induction in differentiated F9 cells suggests that induction is brought about by a novel mechanism using the currently identified regulatory domains.

Interferon inhibits Sendai virus-induced cell fusion: an effect on cell membrane fluidity.

Chatterjee, S; Cheung, H C; Hunter, E
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1982 Português
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Interferon can affect several cellular functions, in addition to its antiviral activity. We report here that pretreatment of human cells with homologous interferon significantly inhibits cell fusion induced by Sendai virus and that this refractory state is accompanied by a decrease in cell plasma membrane fluidity. Multinucleate cell formation induced by beta-propiolactone-inactivated Sendai virus in human fibroblast cells (a system in which fusion results from an interaction of the viral glycoprotein with the cell membrane) was inhibited by more than 90% after addition of human interferon for 18-24 hr. This inhibition could be neutralized by antiserum to interferon. Furthermore, inhibitor studies with cycloheximide and actinomycin D clearly indicated that synthesis of protein and RNA is necessary to establish the resistant state. To determine whether the inhibition of Sendai virus-induced cell fusion resulted from interferon-induced changes at the cell plasma membrane, experiments were carried out using the fluorescence probe 1,6-diphenyl-1,3,5-hexatriene, which is capable of sensing molecular motions in the hydrocarbon core of the bilayer structure. A significant decrease in the membrane fluidity of interferon-treated cells was observed. It is likely...

Interferon enhancement of the invasive capacity of Ewing sarcoma cells in vitro

Siegal, Gene P.; Thorgeirsson, Unnur P.; Russo, Raimondo G.; Wallace, Donald M.; Liotta, Lance A.; Berger, Shelby L.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1982 Português
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The ability of interferons to reduce cell proliferation in vitro and in vivo is a well-studied phenomenon. To extend such observations, the effect of interferons on the invasiveness in vitro of human malignant cells derived from a Ewing sarcoma was evaluated. Two related parameters were examined: (i) production of type IV (basement membrane) collagenase and (ii) penetration of human amnion basement membrane and collagenous stroma. After 6 days of treatment with crude fibroblast, leukocyte, or lymphoblastoid interferon at 100 units/ml in serum-free medium, type IV collagenase levels increased 2- to 4-fold per cell relative to those of untreated controls. With homogeneous fibroblast and lymphoblastoid interferons, a 2-fold elevation in type IV collagenase was detected after 2 days, with further increases, occasionally dramatic, occurring on the 4th and 6th day of treatment. The ability of Ewing sarcoma cells to invade human amnion connective tissue was measured after 6 days of treatment with various interferons. Relative to the behavior of untreated controls, crude leukocyte interferon, homogeneous lymphoblastoid interferon, and homogeneous fibroblast interferon at 100 units/ml augmented invasiveness 3-, 17- and 22-fold, respectively...

Interferon production by leukocytes infiltrating the lungs of mice during primary influenza virus infection.

Wyde, P R; Wilson, M R; Cate, T R
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1982 Português
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Lung fluids and leukocytes were obtained from unprimed C3H mice by transpleural lavage at intervals after infection with influenza A/Hong Kong/68 virus and were tested for interferon activity. Lavage fluid interferon titers correlated directly with lung virus titers and with initial increases in leukocyte yields from infected lungs. In contrast to cultured lymph node cells from infected animals or leukocytes from lungs of uninfected mice, washed leukocytes obtained from the lungs of mice infected 2 to 6 days earlier produced interferon spontaneously in culture. The physiochemical, biological, and antigenic properties of both the interferon in lavage fluids and that produced by lung lavage leukocytes were similar and characteristics of alpha interferon. Fractionation studies indicated that macrophages and T lymphocytes were primarily responsible for the interferon produced in culture. The early presence and significant numbers of interferon-producing leukocytes in infected lungs suggests that these cells have an early role in defense against influenza virus infection.

Comparation Interferon-Inducing and Antiviral Properties of 2-Amino-5-Bromo-6-Methyl-4-Pyrimidinol (U-25,166), Tilorone Hydrochloride, and Polyinosinic-Polycytidylic Acid

Stringfellow, Dale A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1977 Português
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2-Amino-5-bromo-6-methyl-4-pyrimidinol (U-25,166), polyinosinic acid-polycytidylic acid [poly(I:C)], and tilorone HCl induced high levels of serum interferon in mice. Each consequently protected mice against infection with several viruses. After daily injection of inducer, mice developed a reduced interferon response (hyporeactivity) to each compound. However, hyporeactivity developed more slowly to U-25,166 and poly(I:C) than to tilorone HCl. After onset of hyporeactivity, 5 to 6 days without each inducer were required before normal serum interferon levels could be stimulated. Animals also developed a hyporeactive state as a consequence of Semliki Forest or encephalomyocarditis virus infections. By day 2 of either infection, mice had a suppressed interferon response to tilorone HCl, but remains responsive to poly(I:C) or U-25,166 until day 4. In vivo, poly(I:C) stimulated interferon production in a variety of cells and organs, whereas the tilorone HCl and U-25,166 responses involved a nonlymphoid component of the reticuloendothelial system. In vitro, poly(I:C) induced interferon in a variety of murine cells, U-25,166 was active in murine thymus and spleen organ cultures, and tilorone was inactive. These data indicate that U-25,166 is an interesting low-molecular-weight interferon inducer.

Human Fibroblast Interferon for Clinical Trials: Pharmacokinetics and Tolerability in Experimental Animals and Humans

Billiau, Alfons; De Somer, Piet; Edy, Victor G.; De Clercq, Erik; Heremans, Hubertine
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1979 Português
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Human fibroblast interferon (F-interferon) purified by adsorption on controlled-pore glass was given intramuscularly to patients at daily dosages of up to 20 × 106 units. Serum levels of antiviral activity were low or undetectable. In contrast, reasonably high serum titers were found in patients receiving interferon prepared from leukocytes (L-interferon). Similarly, in rabbits lower serum titers were seen with F-interferon than with L-interferon. These results are at variance with those obtained earlier (V. G. Edy, A. Billiau, and P. De Somer, J. Infect. Dis. 133:A18–A21, 1976). Possible explanations for this discrepancy are discussed. The F-interferon evoked febrile reactions, delayed skin reactivity, and transitory lymphopenia in humans. Some patients developed an allergic state of the reaginic type as evidenced by a weal and flare reaction after intradermal challenge. However, these patients did not show allergic symptoms after intramuscular injections. None of the side effects was severe enough to prohibit continuation of the treatment; most of them seemed to be due to contaminants not removed by the purification method. The possibility is considered that some of the side effects, e.g., delayed skin reactivity, are sufficiently specific to justify identification of the active principals.