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At least 973 records · Page 54Linked to original sources
PubMed2000

Interferons and interferon (IFN)-inducible protein 10 during highly active anti-retroviral therapy (HAART)-possible immunosuppressive role of IFN-alpha in HIV infection.

Interferons play an important, but incompletely understood role in HIV-related disease. We investigated the effect of HAART on plasma levels of IFN-alpha, IFN-gamma, neopterin and interferon-inducible protein 10 (IP-10) in 41 HIV-infected patients during 78 weeks of therapy. At baseline HIV-infected patients had raised levels of both IP-10 and IFN-alpha compared with healthy controls (n = 19), with particularly high levels in advanced disease. HAART induced a marked decrease in levels of both IFN-alpha, neopterin and IP-10, though not to normal concentrations. In contrast, IFN-gamma levels were low throughout the study, and not different from controls. While neopterin and IP-10 remained significantly decreased compared with baseline levels throughout the study, IFN-alpha levels returned to baseline at the end of the study. Persistently high IP-10 and IFN-alpha levels were associated with immunological treatment failure and even high baseline levels of IFN-alpha appeared to predict immunological relapse. Furthermore, we found a markedly suppressive effect of exogenously added IFN-alpha on phytohaemagglutinin-stimulated lymphocyte proliferation in both patients and controls, and this suppressive effect seemed not to involve enhanced lymphocyte apoptosis. Our findings suggest a pathogenic role of IFN-alpha in HIV infection, which may be a potential target for immunomodulating therapy in combination with HAART.

Anti-HIV Agents↗
PubMed2003

Increased serum levels of interferon-gamma-inducible protein 10 and monokine induced by gamma interferon in patients with haemophagocytic lymphohistiocytosis.

We measured serum interferon-gamma-inducible protein 10 (IP-10) and monokine induced by gamma interferon (MIG) levels to investigate the role of these molecules in the pathophysiology of haemophagocytic lymphohistiocytosis (HLH). Serum IP-10 and MIG levels were significantly increased in patients with active HLH compared with those of healthy controls. Serum MIG levels decreased gradually during the course of disease in a patient who recovered without therapy. On the other hand, rapid reduction of MIG and IP-10 levels was observed after chemotherapy in a patient with severe HLH. IP-10 and MIG mRNA expression was enhanced in liver and spleen, and IP-10 mRNA expression was enhanced in bone marrow in the patients, suggesting activated macrophages that infiltrated in these organs as one of the main producers of these cytokines. Serum IP-10 and MIG levels showed a significant correlation with serum IFN-gamma levels. In addition, these chemokines had a significant correlation with fever and serum LDH levels, which are clinical indicators of disease activity of HLH. These results suggest that IP-10 and MIG which are produced by activated macrophages by the stimulation of IFN-gamma, play an important role in the pathophysiology of HLH, by recruitment of activated Th1 cells into the tissues or organs.

Acute Disease↗
PubMed1998

Structural characterisation of N-linked and O-linked oligosaccharides derived from interferon-alpha2b and interferon-alpha14c produced by Sendai-virus-induced human peripheral blood leukocytes.

We have previously isolated and partially characterised the components of a highly purified interferon-alpha (IFN-alpha) preparation produced by Sendai-virus-induced human peripheral blood leukocytes. Nine IFN-alpha species were identified, and two of these were found to be glycosylated [Nyman, T. A., Tölö, H., Parkkinen, J. & Kalkkinen, N. (1998) Identification of nine interferon-alpha subtypes produced by Sendai-virus-induced human peripheral blood leukocytes, Biochem. J. 329, 295-302]. Here, we isolated the N-linked oligosaccharides of IFN-alpha14c and the O-linked chains of IFN-alpha2b, and the glycans were characterised by electrospray tandem mass spectrometry and by specific glycosidase digestions monitored by matrix-assisted laser desorption ionisation time of flight mass spectrometry. The IFN-alpha14c N-glycans were shown to exhibit core-fucosylated biantennary glycans, with about 10% carrying an additional alpha1,3-linked fucose unit at the antennae. The IFN-alpha2b was shown to carry about 50% core type-1 disialyltetrasaccharides, 30% core type-1 monosialyltrisaccharides and 20% core type-2 monosialylpentasaccharides.

Glycosylation↗
PubMed1998

Epidermal interferon-gamma inducible protein-10 (IP-10) and monokine induced by gamma-interferon (Mig) but not IL-8 mRNA expression is associated with epidermotropism in cutaneous T cell lymphomas.

Epidermal infiltration by neoplastic CD4+ T cells is a characteristic histologic feature of early stage mycosis fungoides, the most common type of cutaneous T cell lymphoma (CTCL). The mechanisms involved in epidermotropism are unknown. It has been suggested that the CXC chemokines IL-8 and interferon-gamma inducible protein 10 (IP-10) may play a role, but evidence that these chemokines are produced within the epidermis in epidermotropic CTCL is lacking. In this study skin biopsies from 17 CTCL patients, including 12 mycosis fungoides, four pleomorphic CTCL, and one CD8+ CTCL, were investigated for epidermal IL-8 and IP-10 mRNA expression by RNA in situ hybridization. In addition, the expression of monokine induced by gamma-interferon (Mig) mRNA, a CXC chemokine closely related to IP-10, was studied as well. The expression of IL-8 receptors A and B (CXCR1 and CXCR2, respectively) was investigated by immunohistochemistry. The results were correlated with the number and phenotype of epidermotropic T cells. Epidermal expression of IP-10 and Mig mRNA was detected in 10 of 11 and seven of 11 epidermotropic CTCL, respectively, but not in five nonepidermotropic CTCL biopsies or normal human skin. Epidermal IP-10 and Mig mRNA expression correlated with epidermal infiltration of CD4+ T cells, but not of CD8+ T cells. IL-8 mRNA was demonstrated in the epidermis of only two of 15 CTCL biopsies, and was associated, in both cases, with accumulation of neutrophils. Consistently, immunostaining of the (intraepidermal) T cells with antibodies against CXCR1 and CXCR2 was not observed. In conclusion, the results of this study indicate that IP-10, and to a lesser extent Mig, but not IL-8 is involved in the preferential infiltration of neoplastic CD4+ T cells in CTCL.

Antigens, CD↗
PubMed2001

Method to detect substitutions in the interferon-sensitivity-determining region of hepatitis C virus 1b for prediction of response to interferon therapy.

Substitutions deduced by direct sequencing in the interferon-sensitivity-determining region (ISDR) of hepatitis C virus (HCV) are related to patients' responses to interferon (IFN), but sequencing is time consuming and results are only for the dominant virus. We developed a rapid method to detect such changes. With serum from 50 patients with chronic hepatitis C (genotype 1b) given IFN-alpha, a way to detect changes in ISDR by hybridization with oligonucleotide probes that had a prototype nucleotide sequence of HCV-J was established. Hybridization intensity was expressed as optical density (OD(NS5A)). The method was checked with serum from 100 more patients. In the study of 50 patients, all 21 with the prototype sequences had a high OD(NS5A) (> or = 0.4), and all 8 patients with a mutant-type sequence had low values (< or = 0.2). Twelve (95% confidence interval, 36-81%) of 20 patients with OD(NS5A) of <0.4 and 2 (1%-22%) of 30 patients with OD(NS5A) > or = 0.4 had complete responses (CR). All nine (66%-100%) patients with OD(NS5A) <0.4 and little HCV RNA (<100 kIU/mL) had CR, but none (0%-14%) of the 24 patients with high values from both predictors had CR. In the study of 100 patients, OD(NS5A) and the HCV RNA level were independent predictors of the effects of IFN. By multivariate analysis, the odds ratio for a CR in patients with OD(NS5A) of > or = 0.4 was 0.015 (0. 001-0.190) compared with the other patients (P =.001). In conclusion, our method should be useful in identification of prototype strains, which generally resist IFN therapy.

Amino Acid Substitution↗
PubMed2001

A randomized trial of amantadine and interferon versus interferon alone as initial treatment for chronic hepatitis C.

The aim of this study was to compare, in an open-label study, the efficacy and safety of a combination of interferon (IFN) and amantadine (AMA) with that of IFN alone in previously untreated patients with chronic hepatitis C. A total of 200 patients were randomized to 6 MU of IFN-alpha2a 3 times per week, with 200 mg of AMA daily (n = 99) or to an identical dose of interferon alpha2a (n = 101). Patients were treated for 12 months and observed for 6 months' posttreatment. At the completion of treatment, 28.7% of patients in the monotherapy group and 45.5% in the combination group had a virologic response (P =.014). At 6 months' posttreatment, a sustained virologic response was observed in 16.8% (95% CI: 9-23) of patients with IFN alone versus 29.3% (95% CI: 19-37) of patients who were treated with combination therapy (P =.036). In each of the 2 treatments, genotype was the only predictive parameter for a sustained response. At the logistic regression analysis, therapy and genotype were the only 2 parameters with an independent predictive value. In the combination group, at examination of month 3, hepatitis C virus (HCV)-RNA status had a 97.6% (95% CI: 93-102) positive predictive value and a 50% (95% CI: 37-63) negative predictive value for a sustained virologic clearance. A substantial proportion of naïve patients with chronic hepatitis C have an end-of-treatment and end-of-follow-up virologic and biochemical response to a combination of IFN and AMA. This new treatment appears safe and well tolerated.

Adult↗
PubMed1997

An interferon-gamma-activated site (GAS) is necessary for full expression of the mouse iNOS gene in response to interferon-gamma and lipopolysaccharide.

Mouse macrophages can be stimulated by interferon (IFN)-gamma and bacterial lipopolysaccharide (LPS) to produce nitric oxide (NO) as the result of expression of the inducible NO synthase (iNOS; EC 1.14.13.39) gene. The iNOS gene promoter contains a candidate gamma-interferon-activated site (GAS). In transfection studies reported here, it was demonstrated that a luciferase reporter-gene construct, containing four synthetic copies of the iNOS GAS, was inducible when transfected macrophages were stimulated with either IFN-gamma, LPS, or a combination of the two. Consistent with this finding were other transfection analyses, which showed that responsiveness of the intact iNOS promoter to these same agents was significantly reduced when two conserved nucleotide positions within the GAS were mutated. Oligonucleotide probes, which mimicked the iNOS GAS, formed a complex with proteins that appeared in the nuclei of IFN-gamma or IFN-gamma + LPS-treated macrophages within 30 min of stimulation, as shown by electrophoretic mobility shift assay. LPS alone also caused the the appearance of a nuclear protein capable of binding the iNOS GAS-containing oligonucleotide; however, in contrast to binding induced by IFN-gamma, approximately 2 h of stimulation with LPS were required. The protein bound to the iNOS GAS-containing oligonucleotide reacted specifically with an antibody raised against Stat1a, regardless of the stimulus used. These data collectively support the conclusion that binding of Stat1 alpha to the iNOS promoter's GAS is required for optimal induction of the iNOS gene by IFN-gamma and LPS.

Animals↗
PubMed2003

Characterization of interferon-alpha 13, a novel constitutive murine interferon-alpha subtype.

Type-I interferons (IFNs), also called IFNs-alpha/beta, are a family of cytokines induced by viral infection and are primarily involved in antiviral defense of the cells. IFNs-alpha/beta were also reported to be produced constitutively at low levels in mouse and human cells. These so-called endogenous or constitutive IFNs are thought to exert important homeostatic functions in the uninfected host. By searching IFN genes that were not repressed by the leader protein of Theiler's virus, we identified three uncharacterized IFN-alpha genes that are constitutively expressed in uninfected mouse cells, in vitro and in vivo. Two of these genes corresponded to pseudogenes and were tentatively called IFN-alpha(psi2) and IFN-alpha(psi3). IFN-alpha(psi2) transcripts are the most abundant IFN-alpha transcripts detected in several mouse organs in the absence of viral infection. The third gene codes for a new IFN-alpha subtype called IFN-alpha13, which exhibits acid-stable antiviral activity against Theiler's virus, Mengo virus, and vesicular stomatitis virus. IFN-alpha13 displays unusual characteristics, suggesting that it might have a particular function. Firstly, it is transcribed constitutively, independent of viral infection and of interferon regulatory factor-7 induction. Secondly, it contains two N-glycosylation sites, in contrast to other murine IFN-alpha subtypes that contain either one or no N-glycosylation site. In addition to the genes described here above, several other IFN-alpha subtype genes, including a new gene (IFN-alpha14), were expressed in tissues of uninfected mice. In contrast to IFN-alpha13, IFN-alpha14 was found to lack N-glycosylation and have its expression induced in response to viral infection.

Animals↗
PubMed2003

Interferon regulatory factor-3-mediated activation of the interferon-sensitive response element by Toll-like receptor (TLR) 4 but not TLR3 requires the p65 subunit of NF-kappa.

Interferon regulatory factor (IRF) 3 is a transcription factor that binds the interferon-sensitive response element (ISRE) and is activated by Toll-like receptor 3 (TLR3) and TLR4. We have found that a dominant negative form of I kappa B kinase 2 and a mutant form of I kappa B, which acts as a super-repressor of NF-kappa B, blocked activation of the ISRE by the TLR4 ligand lipopolysaccharide but not the TLR3 ligand poly(I-C). TLR4 failed to activate the ISRE in mouse embryonic fibroblasts bearing a targeted deletion of p65, whereas the response to TLR3 in these cells was normal. The p65 subunit of NF-kappa B was detected in the lipopolysaccharide-activated but not poly(I-C)-activated ISRE-binding complex. Finally, p65 promoted transactivation of gene expression by IRF-3. These results therefore indicate that IRF-3-mediated activation of the ISRE by TLR4 but not TLR3 requires the p65 subunit of NF-kappa B.

Animals↗
PubMed2001

Time course profile and cell-type-specific production of monokine induced by interferon-gamma in Concanavalin A-induced hepatic injury in mice: comparative study with interferon-inducible protein-10.

BACKGROUND: We have previously shown that interferon-inducible protein-10 (IP-10), a chemokine for activated lymphocytes, was specifically induced in the liver of Concanavalin A (Con A)-treated mice. The aim of this study was to investigate the time course profile and cell-type-specific hepatic production of monokine induced by interferon-gamma (MIG), a chemokine which shares its receptor and most of its activity with IP-10, in Con A-treated mice and to compare them with those of IP-10. METHODS: Hepatic mRNA expression of MIG and IP-10 was studied by means of Northern blot analysis and in situ hybridization in Con A-treated mice. The levels of MIG and IP-10 in the serum and culture supernatants of murine hepatoma-, hepatic sinusoidal endothelial cell-, hepatic stellate cell- and macrophage-derived cell lines were determined by means of specific enzyme-linked immunosorbent assays. RESULTS: The serum level of MIG slowly reached a maximum at 12 h after Con A injection and remained elevated for a long time, whereas that of IP-10 reached a maximum at 3 h and declined quickly, a finding supported by Northern blot analysis. Using in situ hybridization, the mRNA of MIG as well as IP-10 was found to be expressed in hepatocytes and hepatic non-parenchymal cells. Similar to IP-10, MIG was produced by hepatoma-, hepatic sinusoidal endothelial cell-, hepatic stellate cell- and macrophage-derived cell lines in vitro. CONCLUSIONS: Although both MIG and IP-10 were produced by hepatocytes and hepatic non-parenchymal cells in Con A-treated mice, the time course profile of MIG was distinguishable from that of IP-10. The fact that hepatic MIG and IP-10 were produced sequentially in this hepatitis model may suggest that a non-redundant role is played by these two chemokines in the process of hepatic necro-inflammation.

Animals↗
PubMed1984

Novel human leukocyte interferon subtype and structural comparison of alpha interferon genes.

In the cDNA library of virus-induced human leukocytes a novel subtype of IFN-alpha gene has been identified and sequenced, named IFN-alpha-N. A comparison of nucleotide sequences within the genes coding for different subtypes of human leukocyte interferon (IFN-alpha) has revealed the natural hybrid structure of individual alpha-IFNs-H,B,F, and N. Certain regions of the genes for IFN-alpha-H,B,F,N show a homology with one of the two structurally distinct groups of leukocyte interferons--either IFN-alpha-A,D or IFN-alpha-C,C1 utilized as reference standards.

Amino Acid Sequence↗
PubMed1991

Tissue distribution of recombinant mouse interferon-gamma and recombinant human interferon-gamma in mice, rats, hamsters, and monkeys.

Homologous (mouse) and heterologous (human) recombinant interferon-gamma (IFN-gamma) interferons were injected intravenously into C57BL/6 mice. After 5 min, the greatest proportion of the human IFN was found in the liver, whereas no mouse IFN was detected in the liver at this time or later. Similar results were found in rats, hamsters, and cynomolgus monkeys. Thus, the tissue distribution of these two recombinant IFN-gamma in the various species is not determined by species specificity but by the physicochemical characteristics of the molecules.

Animals↗
PubMed1993

Interferon induction by viruses. XXII. Vesicular stomatitis virus-Indiana: M-protein and leader RNA do not regulate interferon induction in chicken embryo cells.

Several field isolates, strains, mutants, and revertants of vesicular stomatitis virus (VSV), Indiana (IN) serotype, were studied that differed greatly in their capacity to induce interferon (IFN) in aged chick embryo cells. The predicted M-protein amino acid sequence of a wild-type field isolate that induced > or = 10,000 units/ml IFN in chicken embryo cells was identical to that of a wild-type field isolate that induced < 2 units/ml and of a noninducing wild-type laboratory strain. The 47-base plus-strand leader RNA sequences were the same for five IFN-inducing, and eight noninducing independent isolates of wild-type VSV IN. Our data show that the M-protein and plus-strand leader RNA do not of themselves regulate the induction of IFN in this system. Because the capacity of VSV IN to induce IFN resides in virion-associated elements (Marcus and Sekellick, 1987, J. Interferon Res. 7, 269-284), the differences in IFN yield observed with various isolates must result from changes in other virion components that remain to be determined.

Amino Acid Sequence↗
PubMed1995

Priming with interferon-alpha 1 or interferon-alpha 2 enhances the production of both subtypes simultaneously.

A short period of incubation with interferon-alpha ("priming") increases the amounts of IFN-alpha formed by human peripheral blood leukocytes when subsequently induced with a virus. We investigated specifically the effect of priming on the production of two individual subtypes, IFN-alpha 1 and IFN-alpha 2. The rate of interferon synthesis and the amounts formed were equally potentiated in leukocytes primed with either IFN-alpha 1 or IFN-alpha 2. Whichever of these was used for priming had no selective effect on the relative increased production of IFN-alpha 1 or IFN-alpha 2.

Antibodies, Monoclonal↗
PubMed1996

MTS interferon assay: a simplified cellular dehydrogenase assay for interferon activity using a water-soluble tetrazolium salt.

MTS, a tetrazolium dye, is reduced by hydrogenases in living cells to a water-soluble formazan. When it is added to the medium at the end of a cytopathic effects (CPE) inhibition interferon assay, the formazan formed diffuses into the medium; the resultant optical density directly and quantitatively measures how much cellular damage has been produced by the challenge virus in the presence of different amounts of interferon. The use of MTS has considerable advantages in that after it is added, no further steps, such as washing of the cells, extraction of dye, or other manipulations, are needed.

Cell Line↗
PubMed1987

Characterization of E. coli-derived recombinant human interferon-beta as compared with fibroblast human interferon-beta.

Homogeneous E. coli-derived recombinant human interferon-beta (E. coli-rHuIFN-beta) was characterized in order to elucidate its physicochemical properties, as compared with those of fibroblast human interferon-beta (fibroblast HuIFN-beta). Purified E. coli-rHuIFN-beta and fibroblast HuIFN-beta exhibited a single band of Mr 19,000 and 23,000, respectively, on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The primary structure of E. coli-rHuIFN-beta was identical to the prediction from the cDNA sequence. Furthermore, both the circular dichroism (CD) spectra and the 1H nuclear magnetic resonance (NMR) spectra of E. coli-rHuIFN-beta and fibroblast HuIFN-beta at pH 6.8 were closely similar to each other. On the other hand, on reverse-phase high-performance liquid chromatography (HPLC) using a C18 column, the retention time of E. coli-rHuIFN-beta was longer than that of fibroblast HuIFN-beta. Moreover, although the isoelectric point of E. coli-rHuIFN-beta was pH 8.9, purified fibroblast HuIFN-beta exhibited multiple isoelectric points, probably due to heterogeneity of the carbohydrate moiety. These results indicate that the E. coli-rHuIFN-beta polypeptide folds similarly to fibroblast HuIFN-beta, and the carbohydrate moiety of natural HuIFN-beta has little influence on higher-order structure but does influence the hydrophobic and the electrostatic properties of the molecule.

Amino Acid Sequence↗
PubMed1996

A possible correlation between interferon-stimulated gene expression and cytogenetic responses in chronic myelogenous leukemia patients treated with alpha-interferon.

We studied the expression of the interferon-stimulated genes (ISGs), ISG-54 and 2',5'-oligoadenylate synthetase (2'-5' OAS), using the reverse transcription-polymerase chain reaction in 22 patients with chronic myelogenous leukemia (CML), who were treated with alpha-interferon (alpha-IFN). At the time of diagnosis, 7 patients (31.8%) showed no detectable expression of either gene, whereas 8 expressed both. The remaining 7 expressed neither ISG-54 nor 2'-5' OAS. After alpha-IFN treatment, 5 of the 7 CML patients who had not previously express ISGs expressed either ISG-54 or 2'5' OAS or both and 6 of the 7 who had previously expressed either ISG-54 or 2'-5' OAS expressed both. Three of the 7 (42.9%) CML patients who expressed both genes before and after alpha-IFN administration showed cytogenetic responses, as did 6 of the 11 (54.5%) in whom ISG expression was induced. In contrast, cytogenetic responses occurred in none of the patients in whom ISG expression was not induced. These results suggest that induction of ISG-54 and 2'-5' OAS expression by alpha-IFN may be an indicator of cytogenetic responses and, therefore, of value for monitoring CML patients.

2',5'-Oligoadenylate Synthetase↗
PubMed2004

Isolation and sequence of an interferon-tau-inducible, pregnancy- and bovine interferon-stimulated gene product 15 (ISG15)-specific, bovine ubiquitin-activating E1-like (UBE1L) enzyme.

Bovine (bov) interferon-stimulated gene product 15 (ISG15) is produced in the endometrium in response to conceptus-secreted interferon (IFN)-tau. ISG15 conjugates to endometrial proteins through an enzymatic pathway that is similar to ubiquitinylation. Ubiquitin-activating enzyme 1-like protein (UBE1L) initiates enzymatic conjugation by forming a thioester bond with ISG15, thus preparing it for transfer to the next series of enzymes. The bovUBE1L has not been described. We hypothesized that bovUBE1L was induced by pregnancy and IFN-tau in the endometrium. A 110-kDa protein was purified from bovine endometrial (BEND) cells based on affinity with recombinant (r) glutathione S-transferase (GST)-ISG15. This protein was digested in gel with trypsin. Seven peptides were purified using HPLC, sequenced using liquid chromatography-mass spectroscopy-mass spectroscopy and found to share 43-100% identity with human UBE1L. The full-length bovUBE1L cDNA was isolated from a BEND cell cDNA library, sequenced, and found to share 83% identity with human UBE1L cDNA. Northern blot revealed two mRNAs that were detected in greater (P<0.05) concentrations in endometrium from Day 17-21 pregnant versus nonpregnant cows. Western blots using antihuman UBE1L antibody revealed a similar pattern of pregnancy-associated expression of UBE1L protein in the uterus. The bovUBE1L mRNA was localized, using in situ hybridization, primarily to glandular and luminal epithelium, with more diffuse localization to stroma of the endometrium from pregnant cows. Because bovUBE1L was purified through its interaction with rGST-ISG15 and shares significant amino acid and cDNA sequence identity with human UBE1L, it is concluded that it mediates conjugation of ISG15 to uterine proteins in response to the developing and attaching conceptus.

Amino Acid Sequence↗