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PubMed1997

Structure-activity of type I interferons.

Type I IFNs constitute a family of proteins exhibiting high homology in primary, secondary, and tertiary structures. They interact with the same receptor and transmit signals to cellular nucleus through a similar mechanism, eliciting roughly homogeneous biological activity. Nevertheless, the members of that family, IFN alpha species, IFN beta and IFN omega, due to local differences in the structure sometime show distinct properties. From the reported data it results that even minute changes or differences in the primary sequences could be responsible for a significant variety of biological actions, thus inducing to the hypothesis that Type I IFNs, rather than to be the result of a redundant replication during the evolution play definite roles in the defense of living organisms to foreign agents.

Humans↗
PubMed2004

Mice deficient in the interferon type I receptor have reduced REM sleep and altered hypothalamic hypocretin, prolactin and 2',5'-oligoadenylate synthetase expression.

We report that mice with a targeted null mutation in the interferon type I receptor (IFN-RI), which cannot respond to such IFNs as IFNalpha and IFNbeta, have a 30% reduction in time spent in spontaneous rapid eye movement sleep (REMS) as a consequence of a reduced number of REMS episodes. Time spent in nonrapid eye movement sleep (NREMS) was essentially unaltered in IFN-RI knockouts (KOs) compared to 129 SvEv controls. Body temperature and locomotor activity were similar in both strains of mice. Hypothalamic expression of mRNAs for molecules previously linked to sleep-wake regulation and an IFN-inducible antiviral gene, 2',5'-oligoadenylate synthetase 1a (OAS), were determined by real-time reverse-transcriptase polymerase chain reaction (RT2-PCR). The level of hypocretin A mRNA was elevated in IFN-RI KO mice compared to 129 SvEv mice, while prolactin mRNA and OAS mRNA levels were suppressed. Vasoactive intestinal peptide (VIP) and corticotropin-releasing hormone (CRH) mRNA levels were unchanged relative to controls. Serum prolactin levels were similar in both strains. Results are consistent with the hypothesis that increased hypocretin and reduced prolactin in the hypothalamus of IFN-RI KO mice are responsible for their reduced REMS. In addition, the reduced OAS expression may result in modulation of prolactin receptor signaling and thus contribute to suppression of REMS.

2',5'-Oligoadenylate Synthetase↗
PubMed2007

Expression of biomarkers of interferon type I in patients suffering from chronic diseases.

Interferons (IFNs) are used widely in the treatment of viral infections, tumours and neurological disorders. The aim of this study was to evaluate the endogenous expressions of various IFN-induced compounds [specifically: neopterin (NPT), beta2microglobulin (beta2mg) and 2-5 oligoadenylate synthetase (2-5 OAS)] in patients with various chronic diseases requiring treatment with IFN type I. The results showed that patients with such chronic diseases as hepatitis C virus-associated type II mixed cryoglobulinaemia (MC), chronic hepatitis C (CHC) and relapsing-remitting multiple sclerosis (RRMS) are characterized by different activations of the IFN system. Furthermore, the interindividual variability in baseline levels of IFN-induced biomarkers was higher in patients with chronic diseases than in healthy individuals. When levels of the above biomarkers were measured 24 h after the first injection of IFN in patients with CHC or RRMS, significant increases in expression levels of IFN-induced compounds were recorded but, again, there is a broad range of variability in the degree of increase. Further, a significant inverse correlation between baseline levels of NPT, beta2mg and 2-5 OAS activity and their relative increases after IFN administration was found in patients with CHC or RRMS. Together, the results are consistent with the observation that there is considerable interindividual heterogeneity in the clinical response to IFNs, which suggests that host factors other than disease markers must be taken into account in order to manage and optimize the IFN therapy.

2',5'-Oligoadenylate Synthetase↗
PubMed1991

[Effect of double-stranded RNA and interferon type I on reproduction of cytomegalovirus in human fibroblasts].

Double-stranded RNAs (dsRNA) - larifan and ridostin, and recombinant interferons-alpha-2 and beta-1, manufactured in the USSR, inhibited the reproduction of CMV in cell culture. Antiviral effect depended on concentration of preparations, time of administration and m. o. i. DEAE-dextran enhances antiviral effect dsRNA. DsRNA and interferons added to cells infected with CMV at high m. o. i. enhance the viral reproduction. Among studied preparations highest antiviral effect was shown by natural leucocyte interferon (Egis). It was 10 times more active, than recombinant IFNs and in concentration of 1000 U/ml was comparable to activity of larifan (200 mg/ml).

Antiviral Agents↗
PubMed1987

[Expression of human leukocyte interferon type A in Saccharomyces cerevisiae under the control of regulatory elements of the yeast gene URA3].

Expression of a chromosomal gene for human leucocyte interferon A was obtained due to interaction of 5'-nontranslating region of a cloned interferon gene with the regulatory sequences from UNA3 yeast gene. The sequence of 5'-nontranslating region from interferon gene essential for its expression in yeast is localized within 130 b p. from the initiating codon. Due to increasing of plasmid stability and copy number a 60-fold increase. in interferon yield was obtained in yeast transformants reaching the level of 6 X 10(7) u X 1(-1). The data are presented supposing the existence of functional polycistronic mRNA in yeast.

Base Sequence↗
PubMed2006

The synergistic interaction of interferon types I and II leads to marked reduction in severe acute respiratory syndrome-associated coronavirus replication and increase in the expression of mRNAs for interferon-induced proteins.

Interferon (IFN)-alpha, -beta and -gamma have been shown to be only marginally effective against severe acute respiratory syndrome coronavirus (SARS-CoV) replication in Vero cell lines. We investigated the combination of type I IFNs (IFN-alpha or -beta) and IFN-gamma for antiviral activity and found that such combinations synergistically inhibited SARS-CoV replication in Vero cells, using yield reduction assay and the isobologram and combination index methods of Chou and Talalay for evaluation. The highly synergistic anti-SARS-CoV action of type I IFNs and IFN-gamma parallels the marked increase in 2'-5'-oligoadenylate synthetase and p56 mRNAs following exposure in Vero cells to either IFN-alpha or -beta and IFN-gamma compared with the transcriptional levels obtained after stimulation with either IFN alone. These results demonstrate that SARS-CoV, although only moderately sensitive to the antiviral action of the individual types of IFN, is highly sensitive to a combination of type I and II IFNs, which suggests that such combinations may have potential in the treatment of SARS-CoV infections.

2',5'-Oligoadenylate Synthetase↗
PubMed2002

Interferon type I downregulates human parainfluenza virus type 3-induced major histocompatibility complex class II expression.

Human parainfluenza virus type 3 (HPIV3) induces major histocompatibility complex (MHC) class II expression in a signal transducer and activator of transcription-1 (STAT1)- and class II transactivator (CIITA)-independent manner. Interferon (IFN)-gamma, the potent inducer of MHC class II, on the other hand, requires both STAT1 and CIITA in the induction process. IFN-alpha/beta has been shown to inhibit the IFN-y-induced expression of MHC class II by targeting a step(s) downstream of CIITA. Here we report that IFN-alpha/beta also inhibits the CIITA-independent expression of HPIV3-induced MHC class II. The inhibitory role of IFN-alpha/beta on HPIV3-induced MHC class II was confirmed by using anti-IFN-alpha/beta antibody and mutant cell lines defective in the IFN signaling components STAT1 and STAT2. IFN-alpha/beta inhibits virus-induced MHC class II expression just as it does IFN-gamma-induced MHC class II. The inhibition by IFN-alpha/beta of MHC class II expression may play a regulatory role in virus induced autoimmune disease mediated by MHC class II aberrant expression.

Animals↗
PubMed1991

[Phosphorylation of proteins in cytoplasmic and nuclear fractions of human cells treated with double-helical RNA and human recombinant interferon type I].

The dynamics of protein kinases activity in nuclear and cytoplasmic fractions of human fibroblasts treated by preparations of natural and synthetic dsRNA (ridostin, rifastin, larifan and poly(I).poly(C), DEAE-dextran and dsRNA complexes with DEAE-dextran), as well as by preparations of recombinant alpha-2 and beta-1 interferons was obtained. The early activation of enzymes in treated cells extracts and their presence in dsRNA-activated and nonactivated forms were found. In cytoplasmic cellular fractions treated by interferons the dsRNA dependent protein kinases (nonactivated forms- were prevalent.r In contrast, in dsRNA treated cells or dsRNA complexes with DEAE-dextran treated ones the dsRNA independent protein kinases (activated forms) were found, while dsRNA dependent forms induced by interferons were found at later periods. Nuclear protein kinases are mainly dsRNA independent making possible the supposition of their intracellular activation by incoming dsRNA or interferon-induced formation of ds-structures in cellular nuclei. In phosphorylated proteins spectre the 90, 69, 45-40 and 30-35 kDa polypeptides were found. At early intervals in nuclear fractions was found a nuclease resistant and partially EDTA resistant high molecular phosphorylated complex (120 kDa). The complex is, probably, capable of dissociation to low mol mass components. DEAE-dextran induces strong activation of protein kinases in cytoplasm and nuclei and increases the content of activated forms of enzyme in larifan treated cells.

Cell Nucleus↗
PubMed1985

In vitro production of different interferon types by cloned human NK cells.

Human peripheral blood null cells were conjugated in vitro with K-562 cells and expanded into continuous cell lines using IL-2 containing medium (CM) and periodical restimulation with phytohaemagglutinin (PHA). Most of these lines were made up of granular blasts expressing high natural killer (NK) activity. When analysed for different surface markers, the large majority of the blasts were E rosette+, T3+, Tac+, DR+, Leu7+ with a variable proportion of cells expressing T8 and M1 antigens (range: 20-80%). In contrast, T4 antigen was expressed by the majority of cells of the control cell lines originated in the absence of K-562 cells. Twenty-nine clones were obtained from one of the above lines using the limiting dilution technique and subsequently maintained in CM for 4 months or more. The majority of these clones maintained their cytotoxic potential and were able to produce different interferon (IFN) types (IFN-alpha, IFN-gamma or both) when growing in CM. In addition in a number of selected clones, simultaneous stimulation with PHA and K-562 cells was able to induce or support the production of both IFN types.

Antigens, Surface↗
PubMed1999

Upregulation of CD38 gene expression in leukemic B cells by interferon types I and II.

The activation antigen CD38, which has NAD+ glycohydrolase activity in its extracellular domain, is expressed by a large variety of cell types. Few investigations into the regulation of CD38 expression by physiologic stimuli have been reported. As the CD38 promoter contains potential binding sites for interferon (IFN) regulatory factor-1 (IRF-1), we investigated the influence of IFN type I (alpha and beta) and type II (gamma) on CD38 gene expression of leukemic B cells. Using the IFN-responsive B cell line Eskol, we found by RT-PCR analysis a rapid time-dependent induction in CD38 mRNA (starting at 6 h) with each type of IFN. This induction was independent of protein synthesis, suggesting that CD38 gene activation does not require IRF-1 but is merely under direct transcriptional regulation by latent IFN-inducible factors. mRNA stimulation was followed within 24 h by induction of membrane CD38, which coincided with rises of CD38-specific ectoenzymatic activities, that is, NAD+ glycohydrolase, (A/G)DP-ribosyl cyclase, and cyclic ADP ribose hydrolase activities. IFN failed to induce or upregulate the other CD38-related ectoenzymes analyzed, that is, CD39, CD73, CD157, and PC-1. Similarly, treatment of leukemic cells of patients with B chronic lymphocytic leukemia (B-CLL) with IFN resulted in an increase in CD38 mRNA mirrored by plasma membrane upregulation of CD38 and NAD+ glycohydrolase activity. Further investigation in relation to CD38 gene activation and B-CLL behavior remains to be defined.

ADP-ribosyl Cyclase↗
PubMed1982

Activation of natural cytotoxicity of human peripheral blood mononuclear cells by interferon: a kinetic study and comparison of different interferon types.

Overnight incubation of human peripheral blood mononuclear (PBMN) cells with leucocyte interferon (leucocyte IFN) resulted in a 2-5-fold increase in natural cytotoxicity (NC) against the erythroleukaemic cell line K562. Fibroblast IFN, purified to homogeneity by zinc-chelate chromatography, stimulated NC to the same extent, while partially purified immune IFN was about twice as active. Upon gel filtration of immune IFN, NC stimulating and antiviral activity co-eluted. Treatment of PBMN cells with ammonium chloride buffer (AmCl) abrogated NC nearly completely. Incubation of AmCl-treated cells with leucocyte IFN resulted in a partial regeneration of NC. Kinetic studies revealed that this regeneration required only short exposure to IFN followed by a longer incubation period. The data are interpreted as indicating that in the process of NC activation IFN mainly acts as a trigger for precursor cells to mature into cells with NC.

Ammonium Chloride↗
PubMed2000

CpG-oligodeoxynucleotides enhance T-cell receptor-triggered interferon-gamma production and up-regulation of CD69 via induction of antigen-presenting cell-derived interferon type I and interleukin-12.

Bacterial cytidine-phosphate-guanosine (CpG-DNA) activates antigen-presenting cells (APC) and drives T helper 1 (Th1)-polarized immune responses in the mouse. Claims have been made that CpG-DNA costimulates murine T cells. We examined the direct and indirect effects of CpG-oligodeoxynucleotides (CpG-ODN) on human T-cell activation. CpG-ODN failed to costimulate purified human T cells activated with alpha-CD3 or alpha-T-cell receptor (TCR)alphabeta antibodies. In contrast, CpG-ODN sequence-specifically caused increased expression of CD69 on CD4 and CD8 T cells when peripheral blood mononuclear cells (PBMC) were stimulated via alpha-CD3. CpG-ODN and alpha-CD3 stimulation synergized to induce interferon-gamma (IFN-gamma) in T cells and natural killer (NK) cells, as shown by intracellular fluorescence-activated cell sorter (FACS) staining. These effects of CpG-ODN on human T cells were caused by the release of IFN type I (IFN-I) and interleukin-12 (IL-12) from PBMC. Enhancement of CD69 expression on alpha-CD3-triggered T cells could be reproduced in a coculture transwell system of purified T cells and PBMC, was inhibited by neutralizing antibodies to IFN-I and could be mimicked by adding exogenous IFN-I. Furthermore, neutralization of either IFN-I or IL-12 diminished, and in combination abolished, IFN-gamma production. These findings show that CpG-ODN potentiate TCR-triggered activation of human T cells in an APC-dependent manner.

Adjuvants, Immunologic↗
PubMed1995

Antiviral activity of autocrine interferon-beta requires the presence of a functional interferon type I receptor.

We and others have previously observed that the antiviral effects of autocrine interferon (IFN)-alpha/beta activity cannot be abolished by neutralizing antibodies, even when present to a large excess. This raises the possibility that the major part of autocrine activity is triggered intracellularly, possibly bypassing the transmembrane IFN-alpha/beta receptor. To examine this possibility, cells derived from IFN-alpha/beta Ro/o knockout mice lacking a functional IFN-alpha/beta receptor were stably transformed with pHMB-KbMuIFN beta or pMFG-MuIFN beta plasmids encoding a constitutively expressed murine IFN-beta gene. Four different clones were isolated and examined for resistance to a retrovirus, MFG-LacZ, and to Semliki Forest virus. Despite the production of autocrine IFN-beta at levels inducing high antiviral resistance in control cells, none of the clones displayed antiviral resistance. Thus, despite its failure to be neutralized by potent antiserum, the antiviral activity of autocrine IFN-beta takes place via the transmembrane IFN-alpha/beta receptor, and no additional pathway is involved.

3T3 Cells↗
PubMed1981

Production of immune interferon (type II) in cocultures of mouse peritoneal macrophages and syngeneic tumour cells.

Mouse peritoneal macrophages were activated by coculture with syngeneic methylcholanthrene-induced sarcoma cells [7], which grow as an ascites tumour in C3D2 mice [3]. During 4-5 days of cocultivation tumour cells progressively died, leaving highly activated macrophages. Cell-free supernatant harvested from the cultures contained larger amounts of interferon than either macrophages or tumour cells cultivated alone. Peak activity of interferon occurred on day 2. Non-adherent cells cultivated together with tumour cells did not produce interferon. Removal of all non-adherent cells from macrophage cultures and host cells from tumour cell suspension did not abolish interferon production. The macrophages thus seem to be the interferon-producing cells, but the possibility that the very few remaining lymphocytes may cooperate with the macrophages in interferon production cannot be totally ruled out. The interferon produced could not be inactivated by antibodies against virus-induced interferon and was destroyed by treatment at pH 2, indicating that the interferon was not of the alpha or beta type.

Animals↗
PubMed2005

Murine interferon lambdas (type III interferons) exhibit potent antiviral activity in vivo in a poxvirus infection model.

Human interferon lambdas (IFN-lambdas) (type III IFNs) exhibit antiviral activity in vitro by binding to a receptor complex distinct from that used by type I and type II IFNs, and subsequent signalling through the Janus kinase signal transducers and activators of transcription (STAT) pathway. However, evidence for a function of type III IFNs during virus infection in vivo is lacking. Here, the expression of murine IFN-lambdas by recombinant vaccinia virus (VACV) is described and these proteins are shown to have potent antiviral activity in vivo. VACV expressing murine IFN-lambda2 (vIFN-lambda2) and IFN-lambda3 (vIFN-lambda3) showed normal growth in tissue culture and expressed N-glycosylated IFN-lambda in infected cell extracts and culture supernatants. The role that murine IFN-lambdas play during virus infection was assessed in two different mouse models. vIFN-lambda2 and vIFN-lambda3 were avirulent for mice infected intranasally and induced no signs of illness or weight loss, in contrast to control viruses. Attenuation of vIFN-lambda2 was associated with increases in lymphocytes in bronchial alveolar lavages and CD4+ T cells in total-lung lymphocyte preparations. In addition, vIFN-lambda2 was cleared more rapidly from infected lungs and, in contrast to control viruses, did not disseminate to the brain. Expression of IFN-lambda2 also attenuated VACV in an intradermal-infection model, characterized by a delay in lesion onset and reduced lesion size. Thus, by characterizing murine IFN-lambdas within a mouse infection model, the potent antiviral and immunostimulatory activity of IFN-lambdas in response to poxvirus infection has been demonstrated.

Animals↗