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PubMed2004

Thyroid autoimmunity and dysfunction associated with type I interferon therapy.

Type I interferons are currently used for the treatment of chronic viral hepatitis, multiple sclerosis and several hematological and solid tumors. Side effects are not uncommon, and include multiple alterations in thyroid function, some of which are unrelated to autoimmunity. Review of the literature revealed an overall mean prevalence of incident thyroid dysfunction of 6.2%, hypothyroidism occurring more frequently (3.9%) than hyperthyroidism (2.3%). Destructive thyroiditis characterized by early transient thyrotoxicosis followed by hypothyroidism has also been described. Thyroid dysfunction was mainly subclinical, and spontaneous resolution occurred in almost 60% of patients with or without withdrawal of interferon. Risk factors for developing thyroid abnormalities were female sex and the presence of pre-existing autoimmune thyroiditis. Whether prolonged interferon therapy will increase the likelihood of experiencing thyroid dysfunction, as well as the relationship between incident thyroid autoimmunity and the efficacy of interferon therapy, are still open questions. Although the most-likely explanation for thyroid disease occurring with type I interferon therapy remains an autoimmune reaction or immune system dysregulation, a direct inhibitory effect on thyrocytes may be presumed in patients who developed hypothyroidism without autoimmunity. However, the mechanisms of thyroid damage induced by type I interferons have not yet been clarified in detail. We recommend routine evaluation of serum thyroid-stimulating hormone during interferon therapy. A systematic thyroid assessment is useful only for those patients with pre-existing thyroiditis or incident dysfunction. Although discontinuation of interferon therapy is seldom required, it may be necessary in patients who develop Graves' disease and overt hyperthyroidism.

Autoimmune Diseases↗

PubMed2001

Interferon-kappa, a novel type I interferon expressed in human keratinocytes.

High throughput cDNA sequencing has led to the identification of interferon-kappa, a novel subclass of type I interferon that displays approximately 30% homology to other family members. Interferon-kappa consists of 207 amino acids, including a 27-amino acid signal peptide and a series of cysteines conserved in type I interferons. The gene encoding interferon-kappa is located on the short arm of chromosome 9 adjacent to the type I interferon gene cluster and is selectively expressed in epidermal keratinocytes. Expression of interferon-kappa is significantly enhanced in keratinocytes upon viral infection, upon exposure to double-stranded RNA, or upon treatment with either interferon-gamma or interferon-beta. Administration of interferon-kappa recombinant protein imparts cellular protection against viral infection in a species-specific manner. Interferon-kappa activates the interferon-stimulated response element signaling pathway and a panel of genes similar to those regulated by other type I interferons including anti-viral mediators and transcriptional regulators. An antibody that neutralizes the type I interferon receptor completely blocks interferon-kappa signaling, demonstrating that interferon-kappa utilizes the same receptor as other type I interferons. Interferon-kappa therefore defines a novel subclass of type I interferon that is expressed in keratinocytes and expands the repertoire of known proteins mediating host defense.

Amino Acid Sequence↗

PubMed1986

Modulation of lymphocyte proliferation and immunoglobulin synthesis by interferon-gamma and "type I" interferons.

Interferon (IFN)-alpha and IFN-beta ("type I" IFNs), but not IFN-gamma reduced phytohemagglutinin- or pokeweed mitogen (PWM)-induced proliferation in cultures of human mononuclear leukocytes. Proliferation induced by specific antigens (tuberculin PPD or tetanus toxoid) or by exogenous interleukin 2 (IL-2) was strongly inhibited by type I IFNs and, to a lesser extent, by IFN-gamma as well. Inhibition of proliferation in mitogen-stimulated cultures was not due to a reduced production of IL-2 or to an inhibition of IL-2 receptor expression. Type I IFNs inhibited immunoglobulin (Ig) production in PWM-stimulated unseparated mononuclear cells, whereas IFN-gamma enhanced Ig production in such cultures. In cultures of purified B cells type I IFNs caused a stimulation of Ig production and this B-cell differentiation factor (BCDF)-like activity of IFNs was synergistically enhanced in the presence of IL-2. IFN-gamma produced less BCDF-like activity than type I IFNs. These results show that in some instances type I IFNs can be more potent in affecting functions of cells of the immune system than IFN-gamma.

Antibody Formation↗

PubMed1982

Synergistic activities of type I (alpha, beta) and type II (gamma) murine interferons.

Type I (alpha, beta) and type II (gamma) murine interferons are able to potentiate each other with respect to the inhibition of encephalomyocarditis (EMC) virus and of herpes simplex virus type 1 (HSV-1) multiplication in a murine cell line (DBT). Examination of two double-stranded RNA-dependent enzymes in DBT cells, the 2-5A synthetase and the 67,000 MW protein phosphokinase indicates that mixed interferon preparations act synergistically at least with respect to an increase in the activity of the former enzyme. The results obtained with gamma interferons of different origin and of different specific activity suggest that interferon itself, rather than the lymphokines present in the interferon preparations, is responsible for the synergistic effect.

2',5'-Oligoadenylate Synthetase↗

PubMed1995

Tumor suppressor activity of the human consensus type I interferon gene.

Type I interferons have potent antiproliferative activity both in vitro and in vivo, and their tumor suppressor activity has been suggested. A series of eukaryotic vectors containing a synthetic human consensus type I interferon gene (IFN-con1) under the control of different promoters (cytomegalovirus early promoter, murine metallothionein promoter and the Rous sarcoma virus LTR) were constructed and stably transfected into type I IFN-deficient myelogenous leukemic K562 cells. Constitutive expression of IFNcon1 reverted the malignant phenotype, as indicated by loss of tumorgenicity in nude mice. When stably transformed cells were mixed with parental tumor cells, there was retardation of tumor growth. Constitutive expression of IFNcon1 reverted the malignant phenotype in vitro, as indicated by growth inhibition in culture, and reduction in colony formation on soft agar. Furthermore, IFNcon1 gene expression resulted in elevated erythroid differentiation, growth arrest in S phase and induced apoptosis. Thus the presence of an active IFNcon1 gene overcomes the oncogenic potential of K562 by coordinated modulation of cell proliferation, differentiation and programmed cell death, and it acts as a tumor suppressor in vivo.

Animals↗

PubMed2004

Type I interferon and TNFalpha cooperate with type II interferon for TRAIL induction and triggering of apoptosis in SK-N-MC EWING tumor cells.

Ewing's sarcoma is the second most common human bone tumor in childhood. Here, we investigated the sensitivity of the Ewing tumor cell line, SK-N-MC, to the apoptotic effect of type I (IFNalpha) and type II (IFNgamma) interferons and TNFalpha. We demonstrate that although IFNalpha and TNFalpha alone are unable to induce cell death, they act in synergy with IFNgamma to induce SK-N-MC cell apoptosis. The synergistic induction of apoptosis correlated with the synergistic induction of TNFalpha-related apoptosis-inducing ligand (TRAIL) mRNA and TRAIL protein synthesis as well as of TRAIL secretion. Preparations of inducer-free supernatants from SK-N-MC cells stimulated with combinations of cytokines were shown to be cytotoxic for untreated SK-N-MC cells. This cytotoxicity was partially inhibited by addition of TRAILR2/Fc fusion protein, indicating that the secreted TRAIL mediates, at least in part, the apoptotic effect displayed by the supernatants of stimulated SK-N-MC cells. We have shown that the presence of IFNgamma is required to allow the sustained expression of IRF1 in SK-N-MC cells stimulated by addition of IFNalpha or TNFalpha suggesting that IRF1 plays a role in the synergistic induction of apoptosis by combinations of cytokines. Furthermore, we have shown that inhibition of NF-kappaB activation contributes to the IFNgamma-mediated sensitization to the apoptotic effect of TNFalpha. To our knowledge, this is the first report showing that interferon/cytokine combinations are able to induce TRAIL gene expression and TRAIL protein synthesis and secretion in Ewing sarcoma-derived cells. We believe that the observations reported here might contribute to the development of alternative new approaches to the treatment of Ewing tumors resistant to conventional therapy.

Apoptosis↗

PubMed2006

Complex modulation of cell type-specific signaling in response to type I interferons.

The type I interferons (IFNs) are pleiotropic cytokines that regulate many different cellular functions. The major signaling pathway activated by type I IFNs involves sequential phosphorylation of the tyrosine residues of the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) proteins, providing the primary mechanism through which gene expression is induced. Recent work has shown that the responses are quite complex, as shown by different responses to specific subtypes of type I IFN, activation of kinases in addition to JAKs, patterns of activation of all seven STATs in different cells, and activation of transcription factors other than STATs. The type I IFNs use this complexity to regulate many different biological functions in different types of cells, by activating different specific signals and patterns of gene expression.

Animals↗

PubMedDate not supplied

Effects of phenytoin on the production of interferons: differential effects on type I and type II interferons.

The relative effects of treatment with an anticonvulsant, phenytoin, on the production of interferons were determined for both the murine and human systems. Phenytoin treatment was found to have differential effects on the in vitro production of Type I and Type II interferons. Phenytoin had either no effect (HuIFN-alpha) or an enhancing effect (MuIFN-alpha/beta) on the in vitro production of Type I interferons. In contrast, phenytoin pretreatment had an inhibitory effect on the in vitro production of Type II interferons (IFN-gamma) for both the murine and human systems. Phenytoin appeared to exert its inhibitory effect directly on the IFN-gamma-producing cell and was active even when added as late as 6 h after IFN-gamma induction. This inhibition was not related to a toxic effect of the phenytoin and occurred at phenytoin concentrations which were pharmacologically relevant (10-20 micrograms/ml). The effects of phenytoin on the in vivo production of MuIFN-gamma were also examined. In parallel to the in vitro observations, phenytoin treatment of mice significantly reduced the in vivo induction of MuIFN-gamma. The results raise the possibility that phenytoin therapy in humans may significantly affect the production of HuIFN-gamma.

Animals↗

PubMed2003

Activation of the p70 S6 kinase and phosphorylation of the 4E-BP1 repressor of mRNA translation by type I interferons.

The Type I IFN receptor-generated signals required for initiation of mRNA translation and, ultimately, induction of protein products that mediate IFN responses, remain unknown. We have previously shown that IFNalpha and IFNbeta induce phosphorylation of insulin receptor substrate proteins and downstream engagement of the phosphatidylinositol (PI) 3'-kinase pathway. In the present study we provide evidence for the existence of a Type I IFN-dependent signaling cascade activated downstream of PI 3'-kinase, involving p70 S6 kinase. Our data demonstrate that p70 S6K is rapidly phosphorylated on threonine 421 and serine 424 and is activated during treatment of cells with IFNalpha or IFNbeta. Such activation of p70 S6K is blocked by pharmacological inhibitors of the PI 3'-kinase or the FKBP 12-rapamycin-associated protein/mammalian target of rapamycin (FRAP/mTOR). Consistent with this, the Type I IFN-dependent phosphorylation/activation of p70 S6K is defective in embryonic fibroblasts from mice with targeted disruption of the p85alpha and p85beta subunits of the PI 3'-kinase (p85alpha-/-beta-/-). Treatment of sensitive cell lines with IFNalpha or IFNbeta also results in phosphorylation/inactivation of the 4E-BP-1 repressor of mRNA translation. Such 4E-BP1 phosphorylation is also PI3'-kinase-dependent and rapamycin-sensitive, indicating that the Type I IFN-inducible activation of PI3'-kinase and FRAP/mTOR results in dissociation of 4E-BP1 from the eukaryotic initiation factor-4E (eIF4E) complex. Altogether, our data establish that the Type I IFN receptor-activated PI 3'-kinase pathway mediates activation of the p70 S6 kinase and inactivation of 4E-BP1, to regulate mRNA translation and induction of Type I IFN responses.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Anti-inflammatory action of type I interferons deduced from mice expressing interferon beta.

Type I interferons (IFN) are widely used for the therapeutic treatment of viral infections, tumor growth and various chronic diseases such as multiple sclerosis. Antagonism between type I IFNs and IFN-gamma has been described in cells of the immune system, in particular in the activation of macrophages. To study the systemic effects of type I IFNs we used transgenic mice carrying a human IFN-beta (hIFN-beta) gene under the control of the rat insulin I promoter. These animals expressed high levels of hIFN-beta in beta-pancreatic cells, and the ability of the macrophages to respond to pro-inflammatory stimuli was analyzed. Transgenic mice exhibited an increased extravasation of cells to the peritoneal cavity after eliciting with thioglycollate broth. The expression of the inducible form of nitric oxide synthase and cyclooxygenase-2, two enzymes involved in inflammation, was impaired in transgenic animals challenged with lipopolysaccharide and IFN-gamma. Analysis of the mechanisms leading to this attenuated inflammatory response showed a decrease in the serum levels of TNF-alpha and an inhibition of the activation of the transcription factor NF-KB in various tissues. These results indicate that systemic administration of IFN-beta might influence the response to pro-inflammatory stimuli, in particular through the antagonism of IFN-gamma signaling.

Animals↗

PubMed1980

Mouse fibroblast (type I) and immune (type II) interferons: pronounced differences in affinity for gangliosides and in antiviral and antigrowth effects on mouse leukemia L-1210R cells.

Different interferons can be obtained from the same animal species depending on the cells and (or) the inducers used. Interferons of type I and type II differ not only antigenically but also in molecular weight and stability at low pH. We have investigated whether mouse type I and type II interferons also differ in properties relating to their biological action. We present evidence which suggests that the molecular mechanism leading to antiviral and antigrowth effects induced by both types of interferon in susceptible cells must differ in at least one important step. Antiviral and antigrowth activities of type I but not of type II interferon are both inhibited when gangliosides are added to cell cultures together with the interferon. Whereas type I interferon strongly binds to ganglioside affinity columns and can be eluted with solutions of N-acetylneuraminyllactose, type II interferon passes through such columns unretarded. L-1210 mouse leukemia cells (L-1210S) respond equally well to antiviral and antigrowth activities of type I and type II interferons. Type I interferon-resistant L-1210 cells (L-1210R), derived from L-1210S cells after continuous culture in the presence of mouse fibroblast interferon, lack antiviral and antigrowth response to mouse type I interferon [Gresser, I., Bandu, H.T. & Brouty-Boyé, D. (1974) J. Natl. Cancer Inst. 52, 553-559]. However, these cells display the same sensitivity toward type II interferon as do the parent L-1210S cells from which they were derived and respond equally well to its antiviral and antigrowth activities.

Animals↗

PubMed1995

Reconstitution of a high affinity binding site for type I interferons.

The type I interferon (IFN) receptor complex is assumed to be composed of multiple protein subunits. Recently, two proteins have been identified as potential receptor components, both of which share a high degree of structural homology with the immunoglobulin superfamily. One of these proteins, referred to as the human interferon alpha receptor (IFNAR), has been shown to be involved in interferon signal transduction, but it does not bind IFN with high affinity. A second putative receptor protein, named FLP40, has been cloned from human Daudi cells. Transfection of FLP40 into murine NIH 3T3 cells does not result in high affinity IFN binding. In this study, we demonstrate that when expressed in murine L929 cells neither IFNAR nor FLP40 by themselves are capable of binding human IFN-alpha 8. Co-expression of IFNAR and FLP40 results in cells capable of binding IFN-alpha 8 and IFN-alpha 2. Scatchard analysis of binding demonstrated the presence of high (KD 350 pM) and low (KD 4.0 nM) affinity binding sites. Binding of radiolabeled IFN-alpha 8 can be competed with either unlabeled IFN-alpha 8 or a recombinant form of human interferon beta, IFN-beta 1b, but not with IFN-gamma. Ligand binding of IFN-alpha 8 can be inhibited by antibodies directed against IFNAR providing further support for a role for this protein in the formation of a ligand binding site. This is the first demonstration indicating that two previously identified IFN receptor proteins, which individually do not bind type I IFN with high affinity, cooperate in the formation of a type I IFN receptor ligand binding complex.

3T3 Cells↗

PubMed2002

Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells.

To determine whether production of type 1 and type 2 cytokines defines discrete stages of natural killer (NK) cell differentiation, cytokine expression was analyzed in human NK cells generated in vitro in the presence of interleukin-15 (IL-15) and/or IL-2 from umbilical cord blood hematopoietic progenitors. Like peripheral NK cells, the CD161(+)/CD56(+) NK cells from these cultures contained a tumor necrosis factor alpha (TNF-alpha)(+)/granulocyte macrophage-colony-stimulating factor (GM-CSF)(+) subset, an interferon gamma (IFN-gamma)(+) subset, mostly included within the former, and very few IFN-gamma(-)/IL-13(+) cells. Instead, most immature CD161(+)/CD56(-) NK cells, detectable only in the cultures with IL-2, produced IL-13, TNF-alpha, and GM-CSF, but not IFN-gamma, and contained an IL-5(+) subset. In short-term cultures with IL-12 and feeder cells, a proportion of the immature cells acquired the ability to produce IFN-gamma. Part of these produced both IFN-gamma and IL-13, irrespective of induced CD56 expression. These in vitro data indicate that ability to produce the type 2 cytokines IL-13 and IL-5 defines CD161(+) NK cells at intermediate stages of differentiation, and is lost upon terminal functional differentiation, concomitant with acquired ability to produce IFN-gamma.

Cell Differentiation↗

PubMed1998

Bovine type I interferon receptor protein BoIFNAR-1 has high-affinity and broad specificity for human type I interferons.

The type I interferon receptor (IFNAR) is composed of two transmembrane polypeptides, IFNAR-1 and IFNAR-2. Human IFNAR-1 has low intrinsic affinity for IFNs, but enhances the affinity for IFNs of the complex over that of HuIFNAR-2 alone, and modulates the ligand specificity. Bovine cells respond to human alpha interferons. The bovine homologue of HuIFNAR-1, BoIFNAR-1, when expressed in heterologous cells, confers high-affinity binding and broad specificity for human type I IFNs. A soluble fusion protein of the ectodomain of BoIFNAR-1 and an immunoglobulin Fc domain was produced. In contrast to HuIFNAR-1, this protein competes strongly with human cells for IFN binding, and directly binds a wide spectrum of human type I IFNs, including diverse IFN-alphas, IFN-beta and IFN-omega, with moderate to high affinity. This accounts for much of the specificity for human IFNs possessed by bovine cells, with several exceptions. The BoIFNAR-1 ectodomain, in contrast to HuIFNAR-1, may be useful for studies of binary and ternary complexes with IFNs and IFNAR-2, and for purification, assay and biological neutralization protocols.

Animals↗

PubMed2006

Attenuating mutations in the P/C gene of human parainfluenza virus type 1 (HPIV1) vaccine candidates abrogate the inhibition of both induction and signaling of type I interferon (IFN) by wild-type HPIV1.

Recombinant human parainfluenza virus type 1 (HPIV1) and mutants containing point and deletion (Delta) mutations in the P/C gene (r-CDelta10-15HNT553A, r-CR84G, r-CF170S and r-CDelta170), which have previously been evaluated as HPIV1 vaccine candidates, were evaluated for their effect on the type I interferon (IFN) response in vitro. HPIV1 wt infection inhibited the IFN response by inhibiting IFN regulatory factor-3 (IRF-3) activation and IFN production in A549 cells and IFN signaling in Vero cells. In contrast, r-CR84G, r-CF170S and r-CDelta170 were defective for inhibition of IRF-3 activation and IFN production and r-CF170S and r-CDelta170 did not inhibit IFN signaling. Thus, HPIV1 antagonizes the IFN response at both the level of induction and signaling, and antagonism at both levels was disrupted by mutations in the P/C gene. Because CF170S affects C and not P, the anti-IFN function can be attributed to the C proteins. These data, in the context of previous in vivo studies, suggest that the loss of antagonism of the IFN response at both the level of induction and signaling, observed with the P/C mutants, r-CF170S and r-CDelta170, was necessary for significant attenuation in African green monkeys (AGMs).

Animals↗

PubMed1979

Immune-type interferon-induced transfer of viral resistance.

Mouse immune-type interferon (type II), a lymphokine, caused the transfer of viral resistance from mouse L cells to human WISH cells. The interferon was incapable of protecting WISH cells in the absence of L cells. The transfer of viral resistance occurred with interferon preparations of various specific activities, and was in proportion to the interferon concentration in the preparations. The transferred resistance had the characteristics of an interferon-induced antiviral state in that it was blocked by actinomycin D, effective against different types of viruses, and resulted from an action on the cell rather than on the virus. Mouse immune-type interferon was more efficient than virus-type (type I) at eliciting the transfer of protection. The transfer phenomenon may represent a mechanism for amplification of the interferon system as a host defense against viral infection. Further, it serves as a model for studying the mechanism of lymphokine-induced transfer of information between cells.

Animals↗

PubMed2004

Potent inhibition of SARS-associated coronavirus (SCOV) infection and replication by type I interferons (IFN-alpha/beta) but not by type II interferon (IFN-gamma).

We sought to investigate the anti-severe acute respiratory syndrome (SARS)-associated coronavirus (SCoV) activities of type I (alpha and beta) and type II (gamma) interferons (IFN) in vitro. Type I IFNs protected cells from cytopathic effects (CPE) induced by SCoV, and inhibited viral genomic RNA replication in FRhk-4 cells (measured by quantitative RT-PCR) in a dose-dependent manner. Intracellular viral RNA copies were reduced 50% by IFN-alpha at a concentration of 25 U/ml and by IFN-beta at a concentration of 14 U/ml. IFN-gamma had fewer effects on inhibition of viral infection and replication. The type I IFN receptor signaling pathway in host cells is mainly involved in the inhibition of SCoV infection and replication. Type I IFNs could be used as potential agents for anti-SARS treatment.

Antiviral Agents↗

PubMed2007

Role of interferon regulatory factor 3 in type I interferon responses in rotavirus-infected dendritic cells and fibroblasts.

The main pathway for the induction of type I interferons (IFN) by viruses is through the recognition of viral RNA by cytosolic receptors and the subsequent activation of interferon regulatory factor 3 (IRF-3), which drives IFN-alpha/beta transcription. In addition to their role in inducing an antiviral state, type I IFN also play a role in modulating adaptive immune responses, in part via their effects on dendritic cells (DCs). Many viruses have evolved mechanisms to interfere with type I IFN induction, and one recently reported strategy for achieving this is by targeting IRF-3 for degradation, as shown for rotavirus nonstructural protein 1 (NSP1). It was therefore of interest to investigate whether rotavirus-exposed DCs would produce type I IFN and/or mature in response to the virus. Our results demonstrate that IRF-3 was rapidly degraded in rotavirus-infected mouse embryonic fibroblasts (MEFs) and type I IFN was not detected in these cultures. In contrast, rotavirus induced type I IFN production in myeloid DCs (mDCs), resulting in their activation. Type I IFN induction in response to rotavirus was reduced in mDCs from IRF-3(-/-) mice, indicating that IRF-3 was important for mediating the response. Exposure of mDCs to UV-treated rotavirus induced significantly higher type I IFN levels, suggesting that rotavirus-encoded functions also antagonized the response in DCs. However, in contrast to MEFs, this action was not sufficient to completely abrogate type I IFN induction, consistent with a role for DCs as sentinels for virus infection.

Animals↗