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PubMed2000

Role of the cytoplasmic domains of the type I interferon receptor subunits in signaling.

Type I interferons are imperative in maintaining a defense against viral infection. These cytokines also play an important role in the control of cell proliferation. These effects are triggered by ligand binding to a specific cell surface receptor. In the present article, we attempt to analyze the advances made in the last four years on type I interferon signaling. This review will focus on the contribution of the cytoplasmic domain of the alpha and betaL chains of the receptor to the activation of the Jak-Stat pathway. We also analyze the possible role of other pathways in interferon signaling.

Animals↗

PubMed1983

Inhibition of ornithine decarboxylase in human fibroblast cells by type I and type II interferons.

Dilution of human fibroblast GM2767 cell cultures into fresh serum-containing growth medium induces ornithine decarboxylase activity 45-fold over a six-hour interval. When the fibroblast cultures are supplemented with human fibroblast alpha-, beta-, or gamma-interferon at the time of dilution into fresh growth medium, the induction of ornithine decarboxylase is inhibited 61%, 90%, and 65%, respectively. beta-Interferon is the most effective type of interferon to inhibit induction of ornithine decarboxylase.

Carboxy-Lyases↗

PubMed2006

Effects of type I interferons on Friend retrovirus infection.

The type I interferon (IFN) response plays an important role in the control of many viral infections. However, since there is no rodent animal model for human immunodeficiency virus, the antiviral effect of IFN-alpha and IFN-beta in retroviral infections is not well characterized. In the current study we have used the Friend virus (FV) model to determine the activity of type I interferons against a murine retrovirus. After FV infection of mice, IFN-alpha and IFN-beta could be measured between 12 and 48 h in the serum. The important role of type I IFN in the early immune defense against FV became evident when mice deficient in IFN type I receptor (IFNAR(-/-)) or IFN-beta (IFN-beta(-/-)) were infected. The levels of FV infection in plasma and in spleen were higher in both strains of knockout mice than in C57BL/6 wild-type mice. This difference was induced by an antiviral effect of IFN-alpha and IFN-beta and was most likely mediated by antiviral enzymes as well as by an effect of these IFNs on T-cell responses. Interestingly, the lack of IFNAR and IFN-beta enhanced viral loads during acute and chronic FV infection. Exogenous IFN-alpha could be used therapeutically to reduce FV replication during acute but not chronic infection. These findings indicate that type I IFN plays an important role in the immediate antiviral defense against Friend retrovirus infection.

Animals↗

PubMed2002

Natural type 1 interferon producing cells in HIV infection.

Natural type 1 interferon producing cells (IPCs) are in the first line of defense against infectious pathogens. Besides the known properties of type 1 interferons in inhibiting human immunodeficiency virus (HIV) replication, the recent characterization of human IPCs and the possibility to purify them for in vitro studies has greatly accelerated the study of their role in HIV infection. The blood IPC numbers and function are decreased in HIV primary infection and in advanced stages of HIV infection. Loss of circulating IPCs correlates with a high HIV viral load and the occurrence of opportunistic infections. Moreover, HIV can directly infect IPCs in vitro, providing a potential explanation for their in vivo depletion. Thus, the balance between IPCs and HIV replication might be critical in determining the control or progression of HIV infection.

AIDS-Related Opportunistic Infections↗

PubMed2003

9-cis retinoic acid enhances the antiviral effect of interferon on hepatitis C virus replication through increased expression of type I interferon receptor.

The concentration of type I interferon receptor (IFN-Rc) in the liver is a crucial factor in determining the efficacy of interferon (IFN) therapy in patients with chronic hepatitis C. Retinoic acids (RAs) can enhance the expression of type I IFN-Rc expression. The aim of this study was to investigate whether RAs increase the anti-hepatitis C virus (HCV) effect of IFN through an increase in IFN-Rc. The hepatocellular carcinoma cell line HuH-7 was treated with 10(-7) mol/L all-trans RA (ATRA) and 9-cis RA (9-CRA). Expression of type I IFN-Rc was investigated at both the mRNA and protein levels with the use of real-time quantitative polymerase chain reaction and flow cytometry, respectively. We investigated the anti-HCV effect, using in vitro HCV transfection, by monitoring the level of HCV RNA in the culture medium. ATRA and 9-CRA enhanced the expression of type I IFN-Rc at both the mRNA and protein levels. After IFN-alpha treatment, the activity of 2,5'-oligoadenylate synthetase was enhanced by RAs, and this enhancement was abolished when blocking antibodies had previously been bound to the surface receptors. IFN treatment decreased the concentration of HCV RNA, and this effect was enhanced by treatment with RAs. Our findings suggest that RAs enhance the anti-HCV replication effect of IFN-alpha through up-regulation of type I IFN-Rc in HuH-7 cells.

2',5'-Oligoadenylate Synthetase↗

PubMedDate not supplied

Inhibition of angiogenesis by type I interferons in models of Kaposi's sarcoma.

Kaposi's Sarcoma (KS) is a pathology which occurs with increased frequency and in a particularly aggressive form in AIDS patients. The HIV-1 Tat protein appears to be an important co-factor in the induction of the extensive neo-vascularization associated with AIDS-KS. Tat acts as a chemoattractant for endothelial cells in vitro, inducing both chemotactic and invasive responses. Several clinical trials have been performed testing the effectiveness of diverse biological agents in therapy of KS, among these the type I interferons. Type I IFNs have diverse biological functions besides their anti-viral activity, including anti-angiogenic properties. We have shown that IFN alpha and IFN beta are potent inhibitors of both primary and immortalized endothelial cell migration and morphogenesis in vitro as well as neo-angiogenesis induced by HIV-1 Tat in vivo. The inhibitory effect of IFN class I on HIV-Tat associated angiogenesis further supports its use as a therapy for epidemic Kaposi's sarcoma. The use of recombinant IFNs at the levels required to obtain a therapeutic effect are associated with side effects and toxicity, therefore we are now developing a gene therapy approach for constant and local delivery type I IFNs.

Angiogenesis Inhibitors↗

PubMed1990

Difluoromethylornithine prevents the down-regulation of type I interferon receptors: a possible mechanism for a synergistic antiproliferative effect.

Type I interferon and difluoromethylornithine have been shown to exert an antiproliferative effect, both alone and in combination, in several tumor cell lines. Using B16 melanoma cells, we have shown that these two drugs inhibit growth over 72 hr in vitro. The estimated ED50 values for difluoromethylornithine and type I interferon were 31.1 +/- 1.1 microM and 22.3 +/- 2.7 IU/ml, respectively. When used in combination, a marked synergism was observed, as detected by isobologram analysis. Type I interferon, at concentrations that exhibited synergistic activity with difluoromethylornithine, did not affect ornithine decarboxylase activity or intracellular polyamine concentrations. These data suggest that the synergistic antiproliferative effect of murine type I interferon in combination with difluoromethylornithine is not mediated via polyamine depletion. When we examined the type I interferon receptor numbers on the B16 cells exposed to 5 IU/ml murine type I interferon for 72 hr, a 40% decrease was observed, compared with that seen in control cells. Difluoromethylornithine, at 10 microM, did not affect type I interferon receptor numbers. However, when added to the cells in the presence of murine type I interferon, difluoromethylornithine completely inhibited down-regulation, suggesting that down-regulation of the type I interferon receptor is a polyamine-dependent process. These observations may provide a basis for enhancing the therapeutic efficacy of interferon treatment through control of interferon receptor down-regulation.

Animals↗

PubMed1996

Differences in interferon alpha and beta signaling. Interferon beta selectively induces the interaction of the alpha and betaL subunits of the type I interferon receptor.

All Type I interferons (IFNalpha, IFNbeta, IFNomega) bind to the Type I IFN receptor (IFNR) and elicit a common set of signaling events, including activation of the Jak/Stat and IRS pathways. However, IFNbeta selectively induces the association of the alpha subunit of the Type I IFNR with p100, a tyrosyl phosphoprotein, to transduce IFNbeta-specific signals. Using antibodies raised against the different components of the Type I IFNR, we identified p100 as the long form of the beta subunit (betaL subunit) of the Type I IFNR. This was also confirmed in experiments with mouse L-929 cells transfected with truncated forms of betaL. Thus, IFNbeta stimulation of human cells or mouse L-929 transfectants expressing the human alpha and betaL subunits, selectively induces the formation of a signaling complex containing the alpha and betaL subunits of the receptor. The IFNbeta-regulated interaction of the alpha and betaL chains is rapid and transient and follows a similar time course with the tyrosine phosphorylation of these receptor components. These data demonstrate that the signaling specificity for different Type I IFNs is established early in the signaling cascade, at the receptor level, and results from distinct interactions between components of the Type I IFNR.

Animals↗

PubMed1980

Type I and type II interferons: differential antiviral actions in transformed cells.

In transformed mouse embryo cells, type II interferon had much less antiviral activity than type I interferon. In non-transformed cells, the two interferons had similar high activity, Reversal of the phenotype of Moloney sarcoma virus (MSV) transformed cells by sodium butyrate restored their sensitivity to the antiviral action of type II interferon. Additional evidence for a role of the cytoskeletal network in the action of type II interferon is that its antiviral effect is reduced by cytochalasin B, colchicine or vinblastine. MSV-transformed cells, selected for their resistance to the antiviral action of type I interferon, were sensitive to type II interferon. These differences in the effects of type I and II interferon on transformed cells are at present unexplained, but suggest that they have at least partially separate mechanisms of action.

Animals↗

PubMed1980

Differential efficacies of human type I and type II interferons as antiviral and antiproliferative agents.

Treatment of human fibroblast FS-4 cultures with human type II interferon preparations induced the synthesis of at least four proteins that were similar in size to four of the five proteins induced by type I interferons (Mr 120,000, 88,000, 67,000, and 56,000). However, the Mr 67,000 and 56,000 proteins were induced more strongly by type II than by type I interferon, and a counterpart of a Mr 80,000 protein induced by type I interferons was not noticeably induced by type II interferon preparations. We therefore compared type I and type II interferons for relative antiviral activities against different viruses (vesicular stomatitis, encephalomyocarditis, and vaccinia viruses and reovirus) and for cell growth-inhibitory activities on various cell types. The replication of vesicular stomatitis and encephalomyocarditis viruses was inhibited more strongly by type I interferon, whereas reovirus and vaccinia virus showed greater sensitivity to type II interferon preparations. This indicates that viruses may differ in their sensitivity to human type I and type II interferons and that the antiviral mechanisms induced by type I and type II interferons may have significant differences. The type I and type II interferons may have significant differences. The type I and type II interferons may also differ in their efficacies as antiproliferative agents. Type II interferon preparations at 2.5 units/ml inhibited the incorporatin of [3H]thymidine to a greater extent than did type I interferon at 400 units/ml. (For both type I and type II interferons, the unit of interferon activity was defined as the concentration that decreased the yield of vesicular stomatitis virus by 50% in FS-4 cultures.) Furthermore, whereas type II interferon preparations had a reversible cytostatic effect on normal human fibroblasts at 10 units/ml, the transformed cells tested (HeLa, osteosarcoma, U-amnion) showed extensive cell death, thus indicating that it may have a cytocidal effect on certain tumor cells. It appears that human type II interferon (or a factor present in these preparations) may be a potent antitumor agent.

Cell Division↗

PubMed1992

Regulation of gene expression by cytokines and virus in human cells lacking the type-I interferon locus.

A number of genes that are induced by type-I interferons are also activated by one or more other inducers, including double-stranded RNA, viruses, interferon-gamma, interleukin-1 and tumor necrosis factor. However, these inducers can also activate the expression of type-I interferons. Thus, the activation of type-I interferon-inducible genes by these other inducers could be direct, or a secondary consequence of the induction of interferon. To distinguish between these possibilities, we have used cell lines lacking all type-I interferon genes to study the direct effect of potential inducers on the expression of 14 interferon-inducible human genes. We show that double-stranded RNA, virus, interferon-gamma or tumor necrosis factor-alpha can act directly to induce specific subsets of type-I interferon-inducible genes in the absence of any possible type-I interferon involvement. The cis-acting element which confers inducibility by type-I interferon has been shown in some cases to confer inducibility by interferon-gamma, double-stranded RNA or virus as well. However, not all promoters containing such an element respond to both interferon and other inducers. Thus, the ability of a given gene to respond to different inducers most likely depends on the exact nature and specific combination of cis-acting elements present in its promoter.

Animals↗

PubMed1996

Binding of interferon-alpha and -beta to a component of the human type I interferon receptor expressed in simian cells.

The type I interferons (IFNs) are a family of homologous cytokines that compete for receptor binding. Past experiments with a cloned human IFN-alpha receptor component (designated herein as HuIFNAR-1) transfected into different cell backgrounds have given contradictory results in terms of binding and signalling after exposure of cells to different human type I IFNs. In order to investigate the binding specificity of human type I IFN subtypes to HuIFNAR-1, a cDNA encoding HuIFNAR-1 was transfected into simian COS cells. HuIFNAR-1 expression in COS cells, which was confirmed by Northern blot analysis, resulted in increased binding of 125I-labelled HuIFN-alpha 2 and -beta. These data support the participation of this receptor component in ligand binding, probably in association with other receptor components.

Animals↗

PubMed1996

Type I interferon genes and proteins.

The large number of type I interferon genes in mammalian species could be explained by simple redundancy, by different functions for different interferons, or by different spatial or temporal patterns of expression. Different functions would require different receptors for each interferon, while different patterns of expression would require different transcriptional or postranscriptional regulatory mechanisms. It is also necessary to explain when and how this diversity was achieved. Information on comparative genetics of the interferon system, cloning of new interferon genes, studies on receptor interactions and studies on gene expression are accrued at each of the annual meetings of the ISICR. The last meeting held on October 2-7, 1994, at Budapest was not an exception, and this review summarizes some of this year's reports.

Animals↗

PubMed1998

The evolution of the type I interferons.

There are five recognized subtypes within the type I interferons (IFN), IFN-alpha, IFN-beta, IFN-delta, IFN-omega, and IFN-tau, although others may remain to be described, and the IFN-omega may have to be subdivided further because of their evident structural complexity. Together, they constitute an ancient family of intronless genes, possibly present in all vertebrates. THe IFNA/IFNB genes originated by duplication of a progenitor after the divergence of birds, most probably about 250 million years ago (MYA). The avian gene itself proceeded to duplicate to form a series of independent subtypes. The IFND, to date described only in the pig, arose from the IFNA lineage before the emergence of mammals about 180 MYA and might, therefore, be generally distributed in present day species. The IFNB, which occurs as a single gene in primates and rodents, have been duplicated in some other orders. Recent events have produced 10 or more genes in bovid species. The IFNA, which are clustered with the IFNW in humans and cattle, exist as multiple genes in all mammals so far examined as a result of a series of duplication events, some of which occurred recently and, therefore, independently in separate mammalian lineages. The IFNW diverged from the IFNA approximately 130 MYA, just prior to the emergence of mammals, and have continued to duplicate since then. The IFNT, which play a role in reproduction of ruminants, arose from an IFNW within the Artiodactyla suborder about 36 MYA and are found only in the suborder Ruminantia. These genes have also continued to duplicate to form an extensive family. Consequently, their involvement in early pregnancy is a feature of ruminants and not of other mammalian species.

Animals↗

PubMed2006

Functional expression of human type I interferon receptors in the mouse liver.

We expressed human type I interferon (IFN) receptors (IFNAR) in mice and investigated their signaling. Using a hydrodynamics-based delivery method, vectors containing the genes for IFNAR1 and IFNAR2 were transferred into mice. Six hours after gene-transfer, mice were intravenously injected with human IFN-alpha at 10,000 IU. IFNAR1 and IFNAR2 were both expressed in the liver, but not spleen or lung. The receptors were coexpressed in single liver cells. One hour after IFN-alpha injection, the phosphorylation status of signal transducer and activator of transcription factor 1 (STAT1), a key molecule of IFN signaling, was determined. Phosphotyrosine-STAT1 (p-STAT1), localized to the nucleus of IFNAR-expressing cells, was increased in the livers of IFNAR gene-transferred mice but not in control vector-transferred animals. In conclusion, functional human IFNAR can be delivered to the mouse liver, resulting in an increase in p-STAT1 levels following human IFN-alpha stimulation.

Animals↗

PubMed1997

The in vivo expression patterns of individual type I interferon genes in murine cytomegalovirus infections.

Type I interferon (IFN) family has more than 10 structurally related subtypes of alpha IFN (IFNA) genes and a single beta IFN (IFNB) gene. This study examined the expression of MuIFNA1, A4, A5, A6, A9 and MuIFNB mRNAs in the livers and spleens of MCMV-infected mice at 2, 4 and 6 h post infection. The three strains of inbred mice studied were C57BL/6, B6.C-H-28c and BALB/c. B6.C-H-28c strain is a congenic strain of C57BL/6 genomic background. Detection of the specific mRNAs was by an established semiquantitative procedure based on reverse transcription and PCR amplification followed by differential hybridization to specific oligonucleotides. Similar expression patterns of the type I IFN mRNAs were found in C57BL/6 and B6.C-H-28c strains of mice. However, when the genotype was significantly different (BALB/c), a different expression pattern of IFN mRNAs was seen. Differences in the expression patterns of the type I IFN mRNAs was also seen between the livers and spleens of a given mouse strain. Thus, the present study indicates that mouse genotype appears to be a major determinant of the subtype response pattern seen in vivo and that tissue-type can influence the subtype response pattern seen within a given mouse genotype.

Animals↗

PubMed1977

Bovine type II interferon: activity in heterologous cells.

The antiviral and cell growth inhibition spectra of bovine and human interferons are described. The antiviral activity of type II interferon in heterologous cells far exceeded that of the corresponding type I interferon. Antiviral activity of bovine type II interferon parallels cell growth inhibition activity both in thermal inactivation kinetics as well as in the rate of synthesis. Furthermore, the spectrum of antiviral activity against heterologous cells was the same as that seen for cell growth inhibition suggesting that one molecule may mediate both effects. The therapeutic implications of type II interferon prepared in animals for use in human medicine are discussed briefly.

Animals↗

PubMed1998

Prolactin activates Stat1 but does not antagonize Stat1 activation and growth inhibition by type I interferons in human breast cancer cells.

Type I interferons (IFN alpha and IFN beta) are presently used in the adjuvant treatment of several human cancers. However, these cytokines have demonstrated only modest success in breast cancer therapy, and research efforts have focused on improving their efficacy. Recent progress in understanding the molecular mechanisms underlying the antiproliferative effects of IFNs has identified the cytoplasmic transcription factor Stat1 as a critical mediator. It is, therefore, possible that IFN-induced growth inhibition of mammary epithelial cells is counteracted by other cytokines that also use Stat1. One such candidate IFN-antagonist with particular relevance to breast cancer is the mammotropic hormone prolactin (PRL). The main goal of this study was to examine whether PRL would interfere with type I IFN (IFN alpha/beta) signal transduction by competing for limited cytoplasmic Stat factors. A second aim was to test whether pretreatment of mammary tumor cell lines with IFN gamma could enhance the effect of IFN alpha/beta. By analyzing the effect of PRL on IFN alpha/beta-induced tyrosine phosphorylation of Stat proteins and their binding to IFN-regulated genes, we now report that costimulation of PRL receptors did not interfere with IFN alpha/beta signals in several human breast cancer cell lines, including T47D, MCF-7, and BT-20. Specifically, PRL did not affect IFN alpha/beta-induced tyrosine phosphorylation or heterodimerization of Stat1 and Stat2 in any cell line. Instead, IFN alpha/beta- and PRL-induced tyrosine phosphorylation of Stat1 was additive and occurred without evidence of competition for limited concentrations of cytoplasmic Stat1. A similar additive relationship was observed on IFN alpha/beta- and PRL-induced Stat3 tyrosine phosphorylation. Furthermore, electrophoretic mobility shift assays showed that type I IFNs induced predominantly Stat1-Stat2 or Stat1-Stat3 heteromeric complexes with various IFN-response elements of IFN-stimulated genes, whereas PRL induced Stat1 homodimers. Despite significant mutual use of Stats by IFNs and PRL, these results indicated a high degree of signaling specificity in the two receptor systems, and that cytoplasmic levels of Stat proteins were not limiting. Similarly, PRL did not interfere with the growth-inhibitory effect of IFN beta. On the other hand, the study indicated that pretreatment of human breast cancer cell lines with IFN gamma enhanced the growth-inhibitory action of type I IFNs, suggesting a possible avenue for improving the effect of type I IFNs in the treatment of breast cancer patients.

Animals↗