Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “INTERFERON”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,279 records · Page 71Linked to original sources
PubMed1986

Treatment of murine interferon-alpha/beta-sensitive and -resistant friend leukemia cells with tumor necrosis factor in combination with murine interferon-alpha/beta or -gamma.

Interferon-alpha/beta (IFN-alpha/beta)-sensitive (FLC 745) and -resistant (FLC 3Cl8) Friend leukemia cells (FLC) were fairly refractory to the cytotoxicity of murine tumor necrosis factor (MuTNF) in vitro. Both lines became highly sensitive to mTNF when treated in combination with murine IFN-gamma; when treated with IFN-alpha/beta, only the FLC 745 became sensitive to MuTNF. Romeo et al. have reported previously that an antiviral state was induced in both FLC lines by IFN-gamma, but only in FLC 745 by IFN-alpha/beta. The present results suggest that the sensitivity to the synergistic cytotoxic effect of IFN and TNF in these cells is correlated with the ability to be induced into an antiviral state.

Animals↗
PubMed1987

Interferon-alpha A/D blocks an increase in Fc receptors of a human promyelocytic leukemia cell line (HL-60) induced by other recombinant interferons.

The effect of recombinant hybrid interferon (IFN)-alpha A/D either alone or in combination with retinoic acid (RA) on induction of differentiation of the human promyelocytic leukemia cell line HL-60 was studied. The combination of 10 nM RA and IFN-alpha A/D at concentrations of 120 units/ml and higher induces differentiation into cells having many monocytic characteristics such as monocyte-like morphology, ability of superoxide anion production, antibody-dependent cellular cytotoxicity, and nonspecific esterase activity. However, this combination does not induce an increase in IgG Fc receptors (Fc gamma R) and immunoerythrophagocytosis. IFN-alpha A/D alone shows essentially no effect on these parameters. Pretreatment of HL-60 with IFN-alpha A/D blocks the Fc gamma R-increasing activity of IFN-alpha A, IFN-alpha D, and IFN-gamma. This block is complete after a 2-h pretreatment for IFN-alpha A and IFN-alpha D and after a 6-h pretreatment for IFN-gamma. Furthermore, an increase in Fc gamma R-mediated phagocytosis is also suppressed by the pretreatment. However, IFN-alpha A/D does not suppress superoxide anion production. These results indicate that the block of an Fc gamma R-increase by IFN-alpha A/D has not resulted in the competitive inhibition at IFN receptors, but may occur in intracellular events such as postreceptor transduction for the expression of Fc gamma R.

Cell Differentiation↗
PubMed1988

Differential activity of the 30-kD and the 100-kD forms of 2'-5'An synthetase induced by recombinant human interferon-alpha and interferon-gamma.

Two molecular weight variants of the interferon (IFN)-induced intracellular enzyme 2',5'-oligoadenylate (2-5A) synthetase have been described recently; a 100-kD (cytoplasmic) and a 30-kD (intranuclear) form of the enzyme. The 30-kD form has been located primarily in the nucleus, while the 100-kD enzyme was found mainly in the cytoplasm. We examined 2-5A synthetase activity in extracts of human melanoma (Hs294t) cells treated with either recombinant (r) IFN-alpha A or rIFN-gamma to determine the differential regulation of these enzyme subtypes by treatment with the two types of IFN. Cells were treated (continuous exposure) with doses of rIFN-alpha A (1,000 U/ml) or rIFN-gamma (5,000 U/ml), each of which reduced the number of viable cells to 50% of control values (ED50) by day 3 of treatment. At equieffective doses, the maximal increase in 2-5A synthetase occurred at 48 h for both rIFN-alpha A and rIFN-gamma continuous exposure. The maximal 2-5A intracellular activities at 48 h were 800 +/- 40 and 160 +/- 15 nmoles/mg protein for rIFN-alpha A and rIFN-gamma treatment, respectively. High-performance gel permeation chromatography of cell lysates resolved the 2-5A activity into both 100-kD and 30-kD fractions. At 48 h after treatment with rIFN-alpha A, the activity of the 30-kD synthetase was approximately twofold greater than that of the 100-kD enzyme. In contrast, the activity of both 30- and 100-kD enzymes were equivalent 48 h after treatment with rIFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)

2',5'-Oligoadenylate Synthetase↗
PubMed1989

The in vivo antiviral effect of CL246,738 is mediated by the independent induction of interferon-alpha and interferon-beta.

An interferon (IFN) inducer and immunomodulator, CL246,738 [3,6-bis(2-piperidinoethoxy)acridine trihydrochloride], protected mice from lethal infection with Semliki Forest (SFV) and Banzi (BZV) viruses. A single oral dose of CL246,738 (5-150 mg/kg) administered 24 h before intraperitoneal challenge with SFV or BZV fully protected mice from lethal infection. Dose-dependent levels of circulating IFN peaked at 24 h in the serum and peritoneal fluid of CL246,738-treated mice. The circulating IFN of CL246,738-treated mice consisted of IFN-alpha and was produced by spleen cells. Peritoneal exudate cells (PEC) obtained from CL246,738-treated mice produced IFN-beta. Treatment in vivo with anti-IFN-alpha/beta and anti-IFN-beta reversed the protective effect of CL246,738 against lethal SFV encephalitis.

Acridines↗
PubMed1989

Structure-function studies of interferons-alpha: amino acid substitutions at the conserved residue tyrosine 123 in human interferon-alpha 1.

Analogs of human interferon-alpha 1 (IFN-alpha 1) were created in vitro by site-directed mutagenesis to investigate the structural requirements at amino acid position 123 for binding to the IFN receptor, antiviral activity, and antiproliferative activity. The tyrosine residue 123, which is conserved in all known mammalian IFNs-alpha and -beta, was replaced by each of 6 amino acids or was deleted from the protein. Several of the substitutions at position 123 partly or completely abrogated antiviral and antiproliferative activities of human IFN-alpha 1 when human or murine cells were used but not when bovine cells were used. However, with analogs in which amino acids structurally related to tyrosine, phenylalanine, or tryptophan were substituted at position 123, there was retention of antiviral and antiproliferative activities using homologous cells. Thus, although there is not an absolute requirement for tyrosine at position 123, conformational changes associated with alterations of this residue are prejudicial to the biological functions of the IFN-alpha molecule.

Amino Acids↗
PubMed1989

Monoclonal antibodies to the human interferon-gamma receptor: blocking of the biological activities of interferon-gamma and purification of the receptor.

Monoclonal antibodies against the human interferon-gamma (IFN-gamma) receptor were developed by injecting mice with a preparation of receptor that was purified from solubilized placental membranes by ligand affinity chromatography. Three antibodies were identified by their ability to block the binding of 125I-labeled IFN-gamma to its receptor on HeLa cells at 4 degrees C. One of these antibodies blocked several biological activities of IFN-gamma, including its antiviral activity, its ability to induce HLA-DR surface antigens, and its ability to protect cells from NK cell-mediated cytotoxicity. This antibody exhibited higher binding capacity to cells at 37 degrees C and was significantly less displaceable by an excess of IFN-gamma as compared with the other two antibodies. Immunoaffinity chromatography of solubilized crude placental membrane preparation yielded a purified receptor that exhibited a molecular weight of 88,000. The purified receptor retained its ability to bind 125I-labeled IFN-gamma in solution.

Animals↗
PubMed1989

Inhibition of lymphocyte recirculation by murine interferon: effects of various interferon preparations and timing of administration.

The effects of highly purified and/or recombinant interferon (IFN)-alpha/beta, IFN-alpha, IFN-beta, IFN-gamma, and the IFN-inducer, poly(I):poly(C), on the circulation of peripheral blood leukocytes (PBL) and thoracic duct lymphocytes (TDL) of (BALB/cJ x C57Bl/6J)F1 mice were examined. Although all IFN classes could depress significantly the number of circulating PBL and TDL when given at sufficient doses, IFN-alpha appeared to be the most potent. Phenotypic analysis of lymphocytes in the blood and lymph during the decrease induced by IFN suggests that IFN-alpha/beta and IFN-alpha preferentially decrease the Lyt-2+, or suppressor/cytotoxic, subset. Timing of IFN administration was found to be an important factor. Repeated administration of IFN-alpha/beta once a day for 3 days produced continuous suppression of the number of circulating PBL. Administration of either IFN-alpha/beta or IFN-gamma in the evening resulted in a longer and more extensive inhibition of PBL circulation than when IFN was administered in the morning. Our results suggest that the leukopenia observed in many patients undergoing IFN therapy may, in part, be attributed to decreased lymphocyte recirculation, and that the timing of IFN administration may be important in maximizing its therapeutic index.

Animals↗
PubMed1989

Effect of human interferon-alpha and interferon-gamma on growth, histology, and DNA content of human osteosarcomas in nude mice.

The antitumor effect of human natural and recombinant interferon-gamma (IFN-gamma) was evaluated in human osteosarcomas grown as xenografts in nude mice. IFN-gamma was given as daily subcutaneous injections, alone or in combination with IFN-alpha. The growth of two out of three tested osteosarcomas was inhibited by 2 x 10(5) IU of natural IFN-gamma. A five times higher dose of recombinant IFN-gamma, as compared with natural (n) IFN-gamma, was needed to obtain growth inhibition of one osteosarcoma. This difference in dose-response could be explained by differences in pharmacokinetics. Hence, subcutaneously administered natural IFN-gamma gave 10 times higher serum levels than obtained with the recombinant type. Combination treatment with IFN-alpha and IFN-gamma induced a potentiation of the antitumor effect in one osteosarcoma. In another osteosarcoma, 2-4 x 10(5) IU of nIFN-gamma did not effect tumor growth and could not potentiate the antitumor effect of 2-4 x 10(5) IU of nIFN-alpha. By using DNA analysis in cell suspension and tissue section, the proportion of aneuploid tumor cells within the xenograft could be estimated. This analysis showed that the antitumor effects of IFN were more pronounced than mere measurement of tumor volume suggested. IFN-inhibited tumors were partly replaced by fibroblasts or bone tissue. In conclusion, at the doses given nIFN-gamma appeared to have similar antitumor effects as IFN-alpha in two osteosarcomas, whereas one was sensitive to only IFN-alpha. Combination IFN treatment induced a potentiation of the antitumor effect in one osteosarcoma but not in another. The differences between the osteosarcomas in obtained antitumor effect of IFN treatment probably reflects individual IFN sensitivity and demonstrates the importance of assessing several tumors of the same neoplastic entity.

Animals↗
PubMed1990

Effect of calmodulin antagonists on the interferon system: induction and action of interferons.

Synthesis of interferon (IFN) in response to Sendai virus and the development of the resulting antiviral state were studied in human (BG-9) and murine (L-929) fibroblast cell cultures in the presence of the calmodulin antagonists, trifluoperazine (TFP) and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7). Compared to control cultures, 16-fold and 8-fold more IFN was formed in human and murine cells, respectively, when 10 microM TFP was present in the medium for 24 h prior to IFN induction with Sendai virus. W-7 did not affect IFN production in human cells, but enhanced it in L-929 cells by 4- to 8-fold. TFP inhibited the antiviral state induced by homologous IFN in the two cell systems, and at 20 microM, there was a 3,000-fold increase in vesicular stomatitis virus (VSV) yield. It also reduced the maintenance of the antiviral state in human cells. In contrast, W-7 had no effect on the development of the antiviral state in either of the two cell systems. Thus, calcium-calmodulin dependent cellular processes are involved in both induction of IFN and its action. The several patterns response to TFP and W-7 may reflect different ligand-binding sites on calmodulin.

Animals↗
PubMed1990

Interferon-alpha and interferon-beta induce Ia expression in limited protein synthesis condition.

We investigated the regulatory effect of interferons (IFNs) on macrophage (m phi) Ia antigen expression. Unlike type II IFN (IFN-gamma), type I IFNs (IFN-alpha and IFN-beta) were incapable of inducing the accumulation of Ia mRNA. However, when cultured with type I IFN plus cycloheximide (CHX), M phi accumulated significant amounts of Ia-specific mRNA, which was translated into Ia molecules expressed on the cell surface after the removal of CHX. Significant enhancement of Ia mRNA accumulation and the Ia expression were observed also in M phi stimulated with IFN-gamma plus CHX. Type I IFNs suppressed IFN-gamma-dependent Ia expression through the inhibition of Ia mRNA accumulation, but such suppression was not directed to the post-transcriptional step in M phi that had accumulated Ia mRNA in response to stimulation by type I or type II IFN plus CHX. These results seem to indicate that type I IFNs can induce Ia mRNA accumulation but that they also induce some inhibitory protein, the synthesis of which precedes it and is dominant, so that the Ia expression is masked.

Animals↗
PubMed1990

Protein kinase C is involved in the early signals of interferon-alpha but not of interferon-gamma in U937 cells.

Increasing interest is being focused on the role of protein kinase C (PKC) in the mode of action of interferons (IFNs). Here we report that IFN-alpha induced a transient translocation of PKC from the cytosol to the particulate fraction of U937 cells. In contrast, after IFN-gamma treatment, no significant change in PKC activity could be observed. IFN-induced changes in membrane potential were also examined by means of a potential sensitive oxonal dye and flow cytometry. Hyperpolarization was induced by both IFN-alpha and IFN-gamma. The protein kinase inhibitor H-7 blocked the hyperpolarization induced by IFN-alpha but not by IFN-gamma. These concordant results suggest that PKC is involved in the early signals of IFN-alpha but not of IFN-gamma in U937 cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

Interferon-alpha/beta, pentoxifylline, and caffeine synergize with interferon-gamma to induce major histocompatibility complex class I expression on a constitutively class I-negative murine tumor cell line.

The constitutively class I-negative tumor cell line, Kgv, expresses H-2Dk in response to interferon-gamma (IFN-gamma), but not in response to IFN-alpha/beta, tumor necrosis factor, or lymphotoxin. H-2Dk expression was not induced on Kgv cells by the methylxanthines, pentoxifylline (PTX) and caffeine, which modulate class I expression on cells that constitutively express class I molecules. Treatment of Kgv cells with either IFN-alpha/beta, PTX, caffeine, or dibutyryl cAMP and a concentration of IFN-gamma insufficient by itself to induce Dk expression resulted in the induction of Dk expression. Since PTX and caffeine are cAMP-specific phosphodiesterase inhibitors, it is possible that the effects of PTX, caffeine, and dibutyryl cAMP involve a cAMP-dependent mechanism. We conclude that concentrations of IFN-gamma insufficient to induce Dk expression on Kgv cells may be capable of rendering the Dk gene responsive to signals that, in the absence of IFN-gamma treatment, have no effect on Dk expression.

Animals↗
PubMed1993

Antibodies developing against a single recombinant interferon protein may neutralize many other interferon-alpha subtypes.

Three hepatitis C patients out of 15 who received recombinant interferon-alpha 2a (rIFN-alpha 2a) therapy developed high levels of neutralizing antibody coincident with clinical relapse. On analysis, antibodies in their sera were found to also produce some neutralization of lymphoblastoid IFN. Purified lymphoblastoid IFN was separated chromatographically into 10 fractions, each containing one or two IFN-alpha subtypes, and these were used individually to examine the subtype specificity of the neutralizing antibodies in the patients' sera. All three sera neutralized all the subtypes present in the 10 lymphoblastoid IFN fractions. These findings may explain why some patients who develop antibody-mediated resistance to treatment with rIFN-alpha 2 preparations are unable to respond again when treated instead with a human cell derived preparation containing many IFN-alpha subtypes.

Antibody Specificity↗
PubMed1993

Interferon-gamma, but not interferon-alpha beta, synergizes with tumor necrosis factor-alpha and lipid A in the induction of nitric oxide production by murine L929 cells.

Recently, we have demonstrated that tumor necrosis factor (TNF)-sensitive tumor cells produce nitric oxide (NO) in response to TNF whereas TNF-resistant cells do not. Because the addition of interferon-gamma (IFN-gamma) augmented NO production, we were interested in investigating this phenomenon further and comparing the effects of IFN-gamma with those of IFN-alpha beta. We found that cell lines that are sensitive to TNF-mediated cytotoxicity (TMC) produced NO in response to TNF and IFN-gamma, but not in response to IFN-alpha beta. The effect of IFN-gamma on NO production was dose dependent, but IFN-gamma by itself did not induce NO production. A TNF-resistant cell line (MCA) did not produce NO under any of the conditions tested. Different results were obtained when the effect of IFNs on TMC was assayed. TNF-sensitive L929 cells were rendered less sensitive to TNF after treatment with both types of IFN. In contrast, another TNF-sensitive cell, WEHI 164, was rendered more sensitive to TMC after treatment with both types of IFN. The effect of IFNs on WEHI cells was dose dependent. Neither IFN had any effect on TNF sensitivity of TNF-resistant MCA cells. The addition of lipid A (LA) had no effect on TMC under any condition. However, L929 cells treated with LA, TNF, and IFN-gamma produced twice as much NO as cells treated with TNF and IFN-gamma only. Northern analysis for cytokine-inducible NO synthase (NOS) mRNA steady-state levels indicated that TNF synergized with IFN-gamma to induce increased accumulation of NOS mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1993

Interferon-alpha and interferon-gamma induced modulation of proteins in human corneal fibroblasts.

Little is known about the effects of interferon (IFN) on cell function in the eye. We have analyzed the effect of INF-alpha and IFN-gamma on the expression of proteins in cultured human corneal fibroblasts. Treatment with IFN-alpha increased the synthesis of proteins of 84, 76, 52, and 28 kD and decreased the synthesis of a 72-kD protein. Treatment with IFN-gamma increased the synthesis of proteins of 83, 66, 64, 54, and 47 kD. The effect of IFN-alpha and IFN-gamma were first detected at 5-9 h and 9 h, respectively, after the addition of the IFNs and were maximal at 17 and 24 h, respectively. Most of the changes were seen at doses of 1 x 10(1) to 1 x 10(2) U/ml of IFN-alpha or IFN-gamma and were maximal at 1 x 10(2) to 1 x 10(3) U/ml. Thus, each IFN induced distinct proteins based on apparent molecular weight and isoelectric point. These results show that IFN-alpha and IFN-gamma affect the synthesis of small groups of distinct proteins in human corneal fibroblasts.

Cells, Cultured↗
PubMed1993

Consensus interferon induces peak mRNA accumulation at lower concentrations than interferon-alpha 2a.

The biological activity of a novel recombinant interferon, r-metIFN-con1, which represents a consensus sequence of the most commonly appearing amino acids at each locus of 14 naturally occurring IFN-alpha s, was assessed and compared to that of IFN-alpha 2a. The increase in cellular mRNA levels for three IFN-inducible genes served as a quantitative measure of the effectiveness of the stimulation by each of the IFNs. Three cell lines were treated with equimolar amounts of two IFNs encompassing a 5 log range and mRNA was extracted at five different times after treatment. In all cases, r-metIFN-con1 produced mRNA increases at lower concentrations than IFN-alpha 2a. HLA-DR alpha mRNA, which is not affected by IFN-alpha in ME180 or Daudi cells, was also not affected by r-metIFN-con1. However, in Eskol cells, both IFNs effected an increase in HLA-DR alpha mRNA to similar levels. The r-metIFN-con1 was effective at approximately 10-fold lower molar concentrations. At effective concentrations (10-fold lower molar dose of r-metIFN-con1), both IFNs produced similar kinetics of accumulation of all three mRNAs tested. r-metIFN-con1 is therefore more effective than IFN-alpha 2a at the level of mRNA regulation as well as the antiviral and antiproliferative activities that have been reported previously.

Amino Acid Sequence↗
PubMed1993

Interferon action: cytoplasmic and nuclear localization of the interferon-inducible 52-kD protein that is encoded by the Ifi 200 gene from the gene 200 cluster.

Recently, we reported that an interferon (IFN)-inducible, murine 72-kD phosphoprotein (the 204 protein) that is encoded by the Ifi 204 gene from the gene 200 cluster is localized in the nucleolus and the nucleoplasm. We have now raised a polyclonal antiserum against the 202 protein that is encoded by the Ifi 202 gene from the same gene cluster and regions of which are homologous to those from the 204 protein. Using the antiserum, we established that the 202 protein is a 52-kD phosphoprotein whose level in cells from various murine lines can be increased up to 16-fold upon treatment with IFN-alpha. Experiments involving fractionation of cell lysates and indirect immunofluorescence microscopy of cultured cells revealed that the 202 protein was localized in the cytoplasm and the nucleus. Upon treatment of cells with IFN, the 202 protein first accumulated on the surface of a cytoplasmic, membranous fraction and after prolonged treatment with IFN it was localized mainly in the nucleus. In IFN-treated mitotic AKR cells, the 202 protein was colocalized with chromosomes. 202 protein extracted from IFN-treated AKR cells bound double-stranded DNA in vitro. Studies on 202 protein function should be facilitated by the availability of complete cDNA clones and the finding of cell lines and an inbred strain of mice in which the expression of this protein was impaired.

Animals↗
PubMed1993

Stable conformation of an interferon-gamma receptor binding peptide in aqueous solution is required for interferon-gamma antagonist activity.

A peptide antagonist for mouse interferon-gamma (IFN-gamma) activity corresponding to the amino-terminal 39 amino acids of mouse IFN-gamma [MuIFN-gamma (1-39)] has been identified previously. In an analogous manner, we have assessed the ability of the corresponding peptide of human IFN-gamma [HuIFN-gamma (1-39)] to antagonize human IFN-gamma. HuIFN-gamma (1-39) has the ability to block the antiviral activity of human IFN-gamma in a functional assay. In receptor competition, the peptide can also block human IFN-gamma receptor binding. Surprisingly, the murine analog, MuIFN-gamma (1-39), possesses a 10-fold greater ability to block human IFN-gamma antiviral activity and receptor binding than HuIFN-gamma (1-39). Both peptides showed alpha-helical structure in water by circular dichroism, however MuIFN-gamma (1-39) possessed a greater amount of alpha-helix compared to HuIFN-gamma (1-39), suggesting a requirement for a stable secondary structure for optimal antagonist activity. In trifluoroethanol, a helix-stabilizing agent, both peptides showed relatively equal alpha-helices, suggesting that both sequences have an equal potential for helical structure. As IFN-gamma is species specific, the observation that MuIFN-gamma (1-39) can antagonize human IFN-gamma raises questions about the role of this region in species specificity. These studies provide insight into the structural requirements, both primary and secondary, for IFN-gamma receptor binding. In the future, this information, along with more detailed three-dimensional structural analyses of the peptides, could prove useful in the rational design of IFN-gamma agonists and antagonists.

Amino Acid Sequence↗