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PubMed1975

Migration inhibitory factor and type II interferon in the circulation of mice sensitized with mycobacterial components.

Migration inhibitory factor (MIF) and type II interferon were released into the circulation after mice had been sensitized i.v. with a bacillus of Calmette and Guerin (BCG) cell-wall-in-oil vaccine and then challenged four weeks later with 50 mg old tuberculin. At least two components of BCG, protein (PPD) and lipid (P-3), have been identified which are essential for the type of sensitization in which mediators are released after appropriate challenge. The route of sensitization had a marked effect on the development of delayed footpad reactions, release of lymphokines, and resistance to infection with virulent tubercle bacilli. Sensitization by the subcutaneous route tended to induce more pronounced delayed footpad reactions, whereas the i.v. route of sensitization was associated with maximum release of mediators. A close correlation existed between the conditions of sensitization that resulted in maximum production of lymphokines (MIF and Type II interferon) and those that caused protection against aerosol challenge with a virulent strain of Mycobacterium tuberculosis.

Animals↗

PubMed2005

The evolution of the Sin1 gene product, a little known protein implicated in stress responses and type I interferon signaling in vertebrates.

BACKGROUND: In yeast, birds and mammals, the SAPK-interacting protein 1 (Sin1) gene product has been implicated as a component of the stress-activated protein kinase (SAPK) signal transduction pathway. Recently, Sin1 has also been shown to interact with the carboxyl terminal end of the cytoplasmic domain of the ovine type I interferon receptor subunit 2 (IFNAR2). However, the function of Sin1 remains unknown. Since SAPK pathways are ancient and the IFN system is confined to vertebrates, the organization of the Sin1 gene and the sequences of the Sin1 protein have been compared across a wide taxonomic range of species. RESULTS: Sin1 is represented, apparently as a single gene, in all metazoan species and fungi but is not detectable in protozoa, prokaryotes, or plants. Sin1 is highly conserved in vertebrates (79-99% identity at amino acid level), which possess an interferon system, suggesting that it has been subjected to powerful evolutionary constraint that has limited its diversification.Sin1 possesses at least two unique sequences in its IFNAR2-interacting region that are not represented in insects and other invertebrates. Sequence alignment between vertebrates and insects revealed five Sin1 strongly conserved domains (SCDs I-V), but an analysis of any of these domains failed to identify known functional protein motifs. SCD III, which is approximately 129 amino acids in length, is particularly highly conserved and is present in all the species examined, suggesting a conserved function from fungi to mammals. The coding region of the vertebrate Sin1 gene encompasses 11 exon and 10 introns, while in C. elegans the gene consists of 10 exons and 9 introns organized distinctly from those of vertebrates. In yeast and insects, Sin1 is intronless. CONCLUSIONS: The study reveals the phylogeny of a little studied gene which has recently been implicated in two important signal transduction pathways, one ancient (stress response), one relatively new (interferon signaling).

Adaptor Proteins, Signal Transducing↗

PubMed2006

Type 1 interferons and the virus-host relationship: a lesson in détente .

The interface between an infectious agent and its host represents the ultimate battleground for survival: The microbe must secure a niche for replication, whereas the host must limit the pathogen's advance. Among the host's arsenal of antimicrobial factors, the type 1 interferons (IFNs) induce potent defense mechanisms against viruses and are key in the host-virus standoff. Viruses have evolved multiple tricks to avoid the immediate antiviral effects of IFNs and, in turn, hosts have adapted use of this innate cytokine system to galvanize multiple additional layers of immune defense. The plasticity that exists in these interactions provides us with a lesson in détente.

Animals↗

PubMed2002

Humoral immune response and protection from viral infection in mice vaccinated with inactivated MHV-68: effects of type I interferon.

Infection of mice by murine gammaherpesvirus 68 (MHV-68) represents a suitable animal model in which to investigate the immune response against gammaherpesviruses and to test the efficacy of vaccination strategies. In this study, we evaluated the efficacy of heat-inactivated MHV-68 as a vaccine as well as the adjuvant activity of type I interferon (IFN-I) administered together with the vaccine. Mice vaccinated with inactivated MHV-68 and subsequently infected with the virus exhibited a significant augmentation of the virus-specific humoral immune response and a considerable inhibition of MHV-68 acute replication in the lungs compared with unvaccinated control mice. The coadministration of IFN-I with inactivated MHV-68 significantly enhanced the humoral immune response elicited by the vaccine by stimulating the production of virus-specific IgG2 antibodies but did not significantly enhance protection from viral challenge. We conclude that IFN-I, recently shown to exhibit a powerful adjuvant activity to a poorly immunogenic subunit vaccine in mice, can also enhance the humoral immune response when used as adjuvant of an inactivated viral vaccine, even though this effect is less marked as a result of the strong immune response elicited by the inactivated virus alone, which may also involve the contribution of endogenous IFN.

Animals↗

PubMed2006

The murine liver is a potential target organ for IL-19, IL-20 and IL-24: Type I Interferons and LPS regulate the expression of IL-20R2.

BACKGROUND/AIMS: The biological functions of the recently discovered IL-10-related cytokines IL-19, IL-20, IL-22, IL-24 and their receptors IL-20R1, IL-20R2 and IL-22R are not clear. Therefore, the expression of these cytokines and their receptors in the hepatic acute phase response to LPS was analysed. Type I interferons have important immunomodulatory functions in bacterial infections. We investigated if they influence release and organ-specific expression of TNF, IL-6 and IL-10 and the responsiveness of liver to IL-10 related cytokines during the reaction to LPS in vivo. METHODS: B6 and congenic IFNAR-/- mice were intraperitoneally injected with 5mg/kg LPS. Systemic release of cytokines was quantified by ELISA. Organ-specific expression of cytokines and their receptors was evaluated by (semi quantitative or quantitative) RT-PCR. RESULTS: The cytokines IL-19, IL-22 and the IL-20R2 receptor subunit are up-regulated by LPS in the liver of normal mice. IFNalpha/beta enhance the secretion and expression of IL-6 and IL-10 during the response to LPS, but also the up-regulation of IL-20R2 expression. CONCLUSIONS: We show that the liver is a potential target for IL-19, IL-20 and IL-24. During an LPS response, IFNalpha/beta influence cytokine secretion and expression and possibly the response to IL-19 and IL-24.

Acute-Phase Proteins↗

PubMed2000

Role of type I interferons during macrophage activation by lipopolysaccharide.

Activation of macrophages by bacterial lipopolysaccharide (LPS) is accompanied by the secretion of type I interferons (IFNs) which can act in an autocrine manner. We examined the role of type I IFNs in macrophage responses to LPS using bone marrow-derived macrophages (BMM) from IFNAR1-/- mice, which lack a component of the type I IFN receptor and do not respond to type I IFNs. We found that, unlike wild-type (WT) BMM, LPS-treated IFNAR1-/- cells failed to produce nitric oxide (NO), or express inducible NO synthase (iNOS), indicating that type I IFNs are essential for all LPS-stimulated NO production in BMM. Exogenously added type II IFN (IFNgamma) rescued these responses in LPS-treated IFNAR1-/- BMM. In contrast to effects on NO, type I IFNs negatively regulated respiratory burst activity in LPS-primed BMM. We also found that while type I IFNs mediated the anti-proliferative effects of lower concentrations of LPS, at higher concentrations LPS acted in a type I IFNs-independent manner. Finally, we report that type I IFNs are a survival factor for BMM. Despite this, the ability of LPS to also prevent apoptosis in BMM was independent of type I IFNs. These findings highlight the diverse roles of type I IFNs in mediating LPS-stimulated macrophage responses.

Animals↗

PubMed2005

A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells.

Dendritic cells (DC) produce interleukin-12 (IL-12) in response to Toll-like receptor (TLR) activation. Two major TLR signaling pathways participate in the response to pathogens: the nuclear factor-kappaB (NF-kappaB)-dependent pathway leading to inflammatory cytokine secretion including IL-12 and the interferon (IFN)-dependent pathway inducing type I IFN and IFN-regulated genes. Here we show that the two pathways cooperate and are likely both necessary for inducing an optimal response to pathogens. R-848/Resiquimod (TLR7 ligand in the mouse and TLR7/8 ligand in human) synergized with poly(I:C) (TLR3 ligand) or lipopolysaccharide (LPS; TLR4 ligand) in inducing high levels of bioactive IL-12p70 secretion and IFN-beta mRNA accumulation by mouse bone marrow-derived DC (BM-DC). Strikingly, IL-12p70 but not IL-12p40 secretion was strongly reduced in BM-DC from STAT1(-/-) and IFNAR(-/-) mice. STAT1 tyrosine-phosphorylation, IL-12p35, and IFN-beta mRNA accumulation were strongly inhibited in IFNAR(-/-) BM-DC activated with the TLR ligand combinations. Similar observation were obtained in human TLR8-expressing monocyte-derived DC (moDC) using neutralizing anti-IFNAR2 antibodies, although results also pointed to a possible involvement of IFN-lambda1 (also known as IL-29). This suggests that TLR engagement on DC induces endogenous IFNs that further synergize with the NF-kappaB pathway for optimal IL-12p70 secretion. Moreover, analysis of interferon regulatory factors (IRF) regulation in moDC suggests a role for IRF7/8 in mediating IRF3-independent type I IFN and possibly IL-12p35 synthesis in response to TLR7/8.

Animals↗

PubMed2002

Endogenous type I interferons as a defense against tumors.

We have reviewed the experimental results which indicate that endogenous type I interferon (IFN) present either constitutively or possibly induced by the tumor plays an important role in limiting the development of transplantable tumors in mice. Thus, treatment with potent polyclonal neutralizing antibodies to IFN alpha/beta markedly enhanced the subcutaneous growth, invasiveness and metastases of xenogeneic tumor cells (uninfected or infected with RNA or DNA viruses) in athymic nude mice; enhanced the intraperitoneal transplantability of six different syngeneic murine tumors in three strains of immunocompetent mice; and completely abrogated the resistance of allogeneic C57Bl/6 (H-2(b)) or C3H (H-2(k)) mice to the multiplication of Friend erythroleukemia cells (H-2(d)) in the liver and spleen resulting in the death of most mice. The mechanisms by which mice respond to the injection of relatively few tumor cells appear to be multiple, to depend on the site of tumor growth, to occur early and prior to an immunologic response. Endogenous type I IFN appears to constitute an essential component of these defense mechanisms enabling the host to restrict tumor growth.

Animals↗

PubMed2001

Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo.

Type I interferons (IFN-I) are rapidly induced following infection and play a key role in nonspecific inhibition of virus replication. Here we have investigated the effects of IFN-I on the generation of antigen-specific antibody responses. The data show that IFN-I potently enhance the primary antibody response to a soluble protein, stimulating the production of all subclasses of IgG, and induce long-lived antibody production and immunological memory. In addition, endogenous production of IFN-I was shown to be essential for the adjuvant activity of CFA. Finally, IFN-I enhanced the antibody response and induced isotype switching when dendritic cells were the only cell type responding to IFN-I. The data reveal the potent adjuvant activity of IFN-I and their important role in linking innate and adaptive immunity.

Adjuvants, Immunologic↗

PubMed2001

Activation of the p38 mitogen-activated protein kinase mediates the suppressive effects of type I interferons and transforming growth factor-beta on normal hematopoiesis.

Type I interferons (IFNs) are potent regulators of normal hematopoiesis in vitro and in vivo, but the mechanisms by which they suppress hematopoietic progenitor cell growth and differentiation are not known. In the present study we provide evidence that IFN alpha and IFN beta induce phosphorylation of the p38 mitogen-activated protein (Map) kinase in CD34+-derived primitive human hematopoietic progenitors. Such type I IFN-inducible phosphorylation of p38 results in activation of the catalytic domain of the kinase and sequential activation of the MAPK-activated protein kinase-2 (MapKapK-2 kinase), indicating the existence of a signaling cascade, activated downstream of p38 in hematopoietic progenitors. Our data indicate that activation of this signaling cascade by the type I IFN receptor is essential for the generation of the suppressive effects of type I IFNs on normal hematopoiesis. This is shown by studies demonstrating that pharmacological inhibitors of p38 reverse the growth inhibitory effects of IFN alpha and IFN beta on myeloid (colony-forming granulocytic-macrophage) and erythroid (burst-forming unit-erythroid) progenitor colony formation. In a similar manner, transforming growth factor beta, which also exhibits inhibitory effects on normal hematopoiesis, activates p38 and MapKapK-2 in human hematopoietic progenitors, whereas pharmacological inhibitors of p38 reverse its suppressive activities on both myeloid and erythroid colony formation. In further studies, we demonstrate that the primary mechanism by which the p38 Map kinase pathway mediates hematopoietic suppression is regulation of cell cycle progression and is unrelated to induction of apoptosis. Altogether, these findings establish that the p38 Map kinase pathway is a common effector for type I IFN and transforming growth factor beta signaling in human hematopoietic progenitors and plays a critical role in the induction of the suppressive effects of these cytokines on normal hematopoiesis.

Antigens, CD34↗

PubMed2000

HIV-1 gp41 and type I interferon: sequence homology and biological as well as clinical implications.

HIV-1 gp41-like human type I interferon (IFN) could inhibit lymphocyte proliferation and up-modulate MHC class I and II and ICAM-1 molecule expression. Sequence comparison indicates that a similar epitope RILAV-YLKD exists between N-domain of gp41 and two regions in IFN-alpha(aa29-35 and 113-129), IFN-beta (aa31-37 and 125-138) and IFN-omega (aa29-35 and 123-136), which was shown to form IFN-alpha/beta-receptor binding site. Weak sequence similarity was also found to exist in both regions on gp41 and type I IFN of murine and bovine. Experimental studies indicated that a common immunological epitope exists between gp41 and IFN-alpha and -beta. Antibodies against human IFN-alpha and -beta recognized the common immunological epitope and inhibited gp41-binding to the potential cellular receptor protein p45. Moreover, the polyclonal antibody to IFN-beta completely inhibited gp41-binding to human T, B cells and monocytic cells, while IFN-alpha could only inhibit this binding incompletely. It was interestingly observed that human IFN-beta after preincubating with cells could incompletely inhibit the binding of gp41 to human B cells and monocytic cells, and very weakly inhibit the binding to human T cells, indicating that the receptor for IFN-beta-binding may be involved in gp41 binding. This potential relationship may be based on the amino acid sequence homology in the receptor binding region between gp41 and IFN-beta. It was observed that the increased levels of antibodies against human IFN-alpha and -beta exist in HIV-1-infected individuals and are associated with the common epitope on gp41. Besides, several studies provided experimental evidence that the common immunological epitope could induce protective activity against HIV-1. The IFN-alpha-based vaccine has showed a significant reduction of disease progression in IFN-alpha-vaccine-treated HIV-infected patients. Recent experimental evidence indicates that gp41 and IFN-beta were involved in downregulation of CCR5 expression and induction of cell activation or signal transduction. Whether it may be performed by a similar mechanism is still to be investigated.

Amino Acid Sequence↗

PubMed1996

Characterization of a gastric tumor cell line defective in MHC class I inducibility by both alpha- and gamma-interferon.

Alpha/beta and gamma type interferons (IFN), act through distinct cell surface receptors and induce transcription of an overlapping sets of genes. MHC class I genes are inducible by both type of interferons. We have analyzed a gastric tumor cell line, AGS, which was completely defective in MHC class I response to interferon-alpha and gamma. Northern blot analysis demonstrated that the lack of IFN response was related with the absence of up-regulation of specific HLA class I mRNA. Electrophoretic mobility shift assays in various tumor cell lines after IFN-alpha and IFN-gamma treatment showed differential binding of the transcriptional factors to MHC class I regulatory elements. Comparison of kappa-B binding activity showed that IFN-alpha and IFN-gamma induced opposite changes in NF-kappa B binding activity in AGS cells, indicating that the absence of MHC class I response in AGS appears to be independent of kappa-B activity. In contrast, there were remarkable differences in the level of transcriptional factor binding to an interferon-responsive sequence element (IRSE), between AGS and other interferon-responsive tumor cell lines. This result suggests that the low level of transcriptional factor binding to IRSE in AGS cells was responsible of the lack of induction of MHC class I antigens. In this context, overlapping factors in the signal transduction pathway of both type I and II interferons may be involved in the non-responsiveness of this gastric carcinoma tumor cell line.

Adenocarcinoma↗

PubMed2003

Type I interferons induce proteins susceptible to act as thyroid receptor (TR) corepressors and to signal the TR for destruction by the proteasome: possible etiology for unexplained chronic fatigue.

In some patients complaining of chronic fatigue such as those suffering from the chronic fatigue syndrome (CFS), no underlying physical cause can be clearly identified and they typically present a normal thyroid function. Several studies indicate a dysregulation in the type I interferons (IFN-alpha/beta) pathway in CFS resulting in a sustained upregulation of 2('),5(')-oligoadenylate synthetases (2-5OAS). Likewise, patients treated with IFN-alpha/beta usually complain of severe fatigue as a limiting side effect. Beside the 2-5OAS, IFN-alpha/beta induce also the expression of three closely related proteins of unknown function termed the 2-5OAS-like (2-5OASL) proteins. The amino acid sequences of the 2-5OASL proteins display 96% identity with the partial sequence of the thyroid receptor interacting protein (TRIP) 14, further contain two typical thyroid hormone receptor (TR) coregulator domains and feature two ubiquitin C-terminal domains. From these observations, we raise the hypothesis that the 2-5OASL proteins are TRIPs capable of, respectively, repressing TR transactivation and/or signaling the receptor for destruction by the proteasome. Such molecular mechanisms could explain the development of a clinical hypothyroid state in presence of a normal thyroid function.

2',5'-Oligoadenylate Synthetase↗

PubMed1999

Protective effects of type I and type II interferons toward Rous sarcoma virus-induced tumors in chickens.

Growth of tumors induced by Rous sarcoma virus (RSV) is controlled by alleles at the major histocompatibility complex locus in chickens, indicating that immunological host defense mechanisms play a major role. We show here that the resistance phenotype of CB regressor chickens can be partially reverted by treating the animals with a monoclonal antibody that neutralizes the major serotype of chicken type I interferon, ChIFN-alpha. Injection of recombinant ChIFN-alpha into susceptible CC progressor chickens resulted in a dose-dependent inhibition of RSV-induced tumor development. This treatment was not effective, however, in CC chickens challenged with a DNA construct expressing the v-src oncogene, suggesting that the beneficial effect of type I interferon in this system resulted from its intrinsic antiviral activity and probably not from indirect immunmodulatory effects. By contrast, recombinant chicken interferon-gamma strongly inhibited tumor growth when given to CC chickens that were challenged with the v-src oncogene, indicating that the two cytokines target different steps of tumor development.

Animals↗

PubMed2006

Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia.

Early viral infection is often associated with lymphopenia, a transient reduction of blood lymphocyte counts long before the onset of clinical symptoms. We have investigated lymphopenia in mice infected with vesicular stomatitis virus (VSV) or treated with the Toll-like receptor (TLR) agonists poly(I:C) and R-848. In all cases analyzed, lymphopenia was critically dependent on type I interferon receptor (IFNAR) signaling. With the use of bone marrow-chimeric mice, radioresistant cells, such as stroma and endothelium, could be excluded as type I interferon (IFN-alpha/beta) targets for the induction of lymphopenia. Instead, adoptive transfer experiments and studies in conditionally gene-targeted mice with a B- or T-cell-specific IFNAR deletion demonstrated that IFN-alpha/beta exerted a direct effect on lymphocytes that was necessary and largely sufficient to induce lymphopenia. Furthermore, after treatment with R-848, we found that other cytokines such as TNF-alpha also played a role in T-cell lymphopenia. Investigation of the molecular mechanism revealed that lymphopenia was mainly independent of G protein-coupled receptors (GPCRs) and chemokines. In an adhesion assay, B cells of poly(I:C)-treated mice showed moderately increased adhesion to ICAM-1 but not to VCAM-1. In conclusion, our data identify a new effect of direct IFN-alpha/beta stimulation of lymphocytes that profoundly affects lymphocyte redistribution.

Animals↗

PubMed1994

Expression of a functional human type I interferon receptor in hamster cells: application of functional yeast artificial chromosome (YAC) screening.

The previously cloned human interferon alpha/beta (Hu-IFN-alpha/beta; Type I interferon) receptor cDNA appears to be only one component of a receptor complex since expression of the cDNA in mouse cells confers sensitivity only to Hu-IFN-alpha B2, but a monoclonal antibody against this cloned receptor subunit inhibits biological activities of Hu-IFN-alpha A, Hu-IFN-alpha B2, Hu-IFN-omega, and Hu-IFN-beta. Here we report that a yeast artificial chromosome (YAC) containing a segment of human chromosome 21 introduced into Chinese hamster ovary (CHO) cells confers upon these cells a greatly enhanced response to Hu-IFN-alpha A and Hu-IFN-alpha B2 as well as an increased response to Hu-IFN-omega, Hu-IFN-alpha A/D(Bgl), andd Hu-IFN-beta. These responses were measured by induction of class I MHC antigens and by protection against encephalomyocarditis virus and vesicular stomatitis virus. Furthermore, these cells exhibit specific high affinity binding of Hu-IFN-alpha A and Hu-IFN-alpha B2, Hu-IFN-beta, and Hu-IFN-omega. The results indicate that all the genes necessary to reconstitute a biologically active Type I human IFN receptor complex are located within the human DNA insert of this YAC clone.

Animals↗

PubMed2004

[Virus-induced expression of type I interferon genes].

Intracellular double-stranded (ds) RNA is a major sign of replication for many viruses. Host mechanisms detect the dsRNA and provoke antiviral responses. Recently, we identified retinoic acid inducible gene-I (RIG-I), which encodes a DExD/H box RNA helicase containing the caspase recruitment domain (CARD) as a critical regulator for dsRNA-induced signaling. The helicase domain with intact ATPase activity is responsible for recognition of dsRNA, and the CARD transmits downstream signals, resulting in the activation of genes including type I interferons. In this review, we discuss the function of RIG-I in antiviral innate immunity.

Adenosine Triphosphatases↗

PubMed2002

STAT3 activation by type I interferons is dependent on specific tyrosines located in the cytoplasmic domain of interferon receptor chain 2c. Activation of multiple STATS proceeds through the redundant usage of two tyrosine residues.

Human type I interferons (IFNs) play an important role in the regulation of antiviral defense mechanisms, immunomodulatory activities, and growth control. Recent efforts have demonstrated the importance of IFNs in the activation of signal transducers and activators of transcription (STATs). The role of STAT1 and STAT2 in IFN-dependent JAK-STAT signaling is well established; however, the role of STAT3 and its activation by IFNs remains unclear. Understanding the IFN-dependent regulation of STAT3 is of increasing interest because recent studies have demonstrated that STAT3 may play a role in cancer. Studies have revealed that STAT3 is constitutively active in a number of cancer cell lines and that overexpression of an active form of STAT3 transforms normal fibroblasts. Therefore, STAT3 exhibits properties indicative of known oncogenes. In this report, we define the role of the type I IFN receptor in STAT3 activation and identify for the first time tyrosine residues present in the cytoplasmic domain of IFNAR2c that are critical for STAT3 activation. The regulation of STAT3 activation by IFNs was measured in a human lung fibrosarcoma cell line lacking IFNAR2c but stably expressing various IFNAR2c tyrosine mutants. We show here that in addition to IFN-dependent tyrosine phosphorylation of STAT3, activation using a STAT3-dependent electrophoretic mobility shift assay and a STAT3-specific reporter can also be demonstrated. Furthermore, we demonstrate that type I IFN-dependent activation of STAT3 proceeds through a novel mechanism that is dependent on two tyrosines, Tyr(337) and Tyr(512), present in IFNAR2c and contained within a conserved six-amino acid residue motif, GxGYxM. Surprisingly, both tyrosines were previously shown to be required for type I IFN-dependent STAT1 and STAT2 activation. Our results reveal that type I IFNs activate multiple STATs via the overlapping usage of two tyrosine residues located in the cytoplasmic domain of IFNAR2c.

Base Sequence↗