125,615 research outputs found

    Interferon-γ acutely augments inhibition of neocortical layer 5 pyramidal neurons

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    BACKGROUND: Interferon-γ (IFN-γ, a type II IFN) is present in the central nervous system (CNS) under various conditions. Evidence is emerging that, in addition to its immunological role, IFN-γ modulates neuronal morphology, function, and development in several brain regions. Previously, we have shown that raising levels of IFN-β (a type I IFN) lead to increased neuronal excitability of neocortical layer 5 pyramidal neurons. Because of shared non-canonical signaling pathways of both cytokines, we hypothesized a similar neocortical role of acutely applied IFN-γ. METHODS: We used semi-quantitative RT-PCR, immunoblotting, and immunohistochemistry to analyze neuronal expression of IFN-γ receptors and performed whole-cell patch-clamp recordings in layer 5 pyramidal neurons to investigate sub- and suprathreshold excitability, properties of hyperpolarization-activated cyclic nucleotide-gated current (Ih), and inhibitory neurotransmission under the influence of acutely applied IFN-γ. RESULTS: We show that IFN-γ receptors are present in the membrane of rat's neocortical layer 5 pyramidal neurons. As expected from this and the putative overlap in IFN type I and II alternative signaling pathways, IFN-γ diminished Ih, mirroring the effect of type I IFNs, suggesting a likewise activation of protein kinase C (PKC). In contrast, IFN-γ did neither alter subthreshold nor suprathreshold neuronal excitability, pointing to augmented inhibitory transmission by IFN-γ. Indeed, IFN-γ increased electrically evoked inhibitory postsynaptic currents (IPSCs) on neocortical layer 5 pyramidal neurons. Furthermore, amplitudes of spontaneous IPSCs and miniature IPSCs were elevated by IFN-γ, whereas their frequency remained unchanged. CONCLUSIONS: The expression of IFN-γ receptors on layer 5 neocortical pyramidal neurons together with the acute augmentation of inhibition in the neocortex by direct application of IFN-γ highlights an additional interaction between the CNS and immune system. Our results strengthen our understanding of the role of IFN-γ in neocortical neurotransmission and emphasize its impact beyond its immunological properties, particularly in the pathogenesis of neuropsychiatric disorders

    The envelope gene of transmitted HIV-1 resists a late interferon gamma-induced block

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    Type I interferon (IFN) signaling engenders an antiviral state that likely plays an important role in constraining HIV-1 transmission and contributes to defining subsequent AIDS pathogenesis. Type II IFN (IFNγ) also induces an antiviral state but is often primarily considered to be an immunomodulatory cytokine. We report that IFNγ stimulation can induce an antiviral state that can be both distinct from that of type I interferon, and can potently inhibit HIV-1 in primary CD4+ T cells and a number of human cell lines. Strikingly, we find that transmitted/founder (TF) HIV-1 viruses can resist a late block that is induced by type II IFN, and the use of chimeric IFNγ- sensitive/resistant viruses indicates that interferon-resistance maps to the env gene. Simultaneously, in vitro evolution also revealed that just a single amino acid substitution in envelope can confer substantial resistance to IFN-mediated inhibition. Thus, the env gene of transmitted HIV-1 confers resistance to a late block that is phenotypically distinct from those previously described to be resisted by env, and is therefore mediated by unknown IFNγ-stimulated factor(s) in human CD4+ T cells and cell lines. This important unidentified block could play a key role in constraining HIV-1 transmission

    Interferon Lambda: A New Sword in Cancer Immunotherapy

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    The discovery of the interferon-lambda (IFN-λ) family has considerably contributed to our understanding of the role of interferon not only in viral infections but also in cancer. IFN-λ proteins belong to the new type III IFN group. Type III IFN is structurally similar to type II IFN (IFN-γ) but functionally identical to type I IFN (IFN-α/β). However, in contrast to type I or type II IFNs, the response to type III IFN is highly cell-type specific. Only epithelial-like cells and to a lesser extent some immune cells respond to IFN-λ. This particular pattern of response is controlled by the differential expression of the IFN-λ receptor, which, in contrast to IFN-α, should result in limited side effects in patients. Recently, we and other groups have shown in several animal models a potent antitumor role of IFN-λ that will open a new challenging era for the current IFN therapy

    Interferon-Γ inhibits DNA synthesis and insulin-like growth factor-II expression in human neuroblastoma cells

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    Interferon-Γ (IFN-Γ) is known to be an antiproliferative, differentiation agent in many cell types, including neuroblastoma. In this study, we determined the effects of IFN-Γ on cellular growth and expression of insulin-like growth factor II (IGF-II) and IGF receptors in the human neuroblastoma cell line SH-SY5Y. Incubation of SH-SY5Y cells in IFN-Γ (20–100 U/ml) induced the formation of long neuritic processes. IFN-Γ treatment also induced decreases in [ 3 H]TdR incorporation, as well as serum-dependent changes in cell number. Treatment with IFN-Γ reduced cell number 33% in the presence of serum but had no effect on cell number in the absence of serum. IGF-II mRNA content was 60% inhibited by IFN-Γ, and was not serum dependent. The concentration of immunoreactive IGF-II in SH-SY5Y conditioned medium was also reduced in the presence of IFN-Γ, to less than half of control levels. In contrast, type I IGF receptor mRNA content was increased more than three-fold after treatment with IFN-Γ and serum. Co-incubation in IFN-Γ (20–100 U/ml) and IGF-II on (3–10 nM) prevented the inhibitory effects of IFN-Γ on [ 3 H]TdR ncorporation in serum-free media. Our results suggest that IFN-Γ may inhibit DNA synthesis and cell growth by interfering with an IGF-II/type I IGF receptor autocrine growth or survival mechanism.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50226/1/490340502_ftp.pd

    Interferon and Biologic Signatures in Dermatomyositis Skin: Specificity and Heterogeneity across Diseases

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    BACKGROUND: Dermatomyositis (DM) is an autoimmune disease that mainly affects the skin, muscle, and lung. The pathogenesis of skin inflammation in DM is not well understood. METHODOLOGY AND FINDINGS: We analyzed genome-wide expression data in DM skin and compared them to those from healthy controls. We observed a robust upregulation of interferon (IFN)-inducible genes in DM skin, as well as several other gene modules pertaining to inflammation, complement activation, and epidermal activation and differentiation. The interferon (IFN)-inducible genes within the DM signature were present not only in DM and lupus, but also cutaneous herpes simplex-2 infection and to a lesser degree, psoriasis. This IFN signature was absent or weakly present in atopic dermatitis, allergic contact dermatitis, acne vulgaris, systemic sclerosis, and localized scleroderma/morphea. We observed that the IFN signature in DM skin appears to be more closely related to type I than type II IFN based on in vitro IFN stimulation expression signatures. However, quantitation of IFN mRNAs in DM skin shows that the majority of known type I IFNs, as well as IFN g, are overexpressed in DM skin. In addition, both IFN-beta and IFN-gamma (but not other type I IFN) transcript levels were highly correlated with the degree of the in vivo IFN transcriptional response in DM skin. CONCLUSIONS AND SIGNIFICANCE: As in the blood and muscle, DM skin is characterized by an overwhelming presence of an IFN signature, although it is difficult to conclusively define this response as type I or type II. Understanding the significance of the IFN signature in this wide array of inflammatory diseases will be furthered by identification of the nature of the cells that both produce and respond to IFN, as well as which IFN subtype is biologically active in each diseased tissue

    AB0125 EXPRESSION OF INTERFERON TYPE I- AND TYPE II-INDUCED GENES IN PATIENTS WITH SJÖGREN'S SYNDROME WITH AND WITHOUT EXTRAGLANDULAR INVOLVEMENT

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    Background:It is well known that Sjögren's syndrome (SjS) is characterized by an upregulation of interferon (IFN)-induced genes. Namely, IFN type I signature has been reported in peripheral blood mononuclear cells (PBMCs) and in salivary glands of patients with this disease. However, few data are available on possible variability of IFN-induced gene upregulation in different clinical phenotypes of SjS.Objectives:To verify whether upregulation of IFN-induced genes is comparable in patients with SjS characterized by different clinical phenotypes, i.e., patients with systemic extraglandular manifestations (EGMs) versus patients with a disease limited to glandular features (GFs) and with widespread pain (WP).Methods:The study population was composed by 11 patients with SjS and EGMs (1 male, age range 18-78 years), and 10 patients with only GFs and WP (all females, age range 46-81 years), all classified according to ACR-EULAR criteria. The prevalence of anti-SSA(Ro) antibodies was 11/11 and 8/10, respectively. Lip biopsy was positive in all cases. Six healthy normal subjects were also included in the study as control population.Four IFN type I- and 5 IFN type II-induced genes were chosen for the study on the basis of previous literature data. Total RNA from each patient and control was isolated from purified PBMCs, followed by cDNA preparation and real time quantitative-PCR (RQ-PCR) analysis, using specific primer/probe sets. For calculation of relative expression, all samples were normalised against expression of a household gene (beta actin). A further normalization was performed against the mean value of relative expression obtained in the normal controls. Final fold change values were determined from the double-normalised values using the 2−ΔΔCT method (Applied Biosystems).Results:Fold change values of gene expression of both IFN type I- and type II-induced genes in PBMCs were different in the two clinical phenotypes of SjS. Fold change values of IFN type I-induced genes appeared strongly higher in patients with EGM, and some of them only moderately increased in those with only GF and WP. The expression of some of IFN type II-induced genes were slightly increased in patients belonging to both clinical phenotypes. Results are detailed in the table.Table.Fold change values of gene expression in patients with SjS plus EGMs, in patients with disease limited to GF and WP, and in controls.GeneMX1IFIT1IFT3IFI44IDO1GRP1MIGIP-10P2RY14SjS-EGMs85.938.524.440.425.18.34.51.55.5SJS-GF-WP4.21.72.04.84.11.20.60.31.3Controls2.11.61.11.51.41.31.51.31.4Legend. IFN type I-induced genes: MIX, IFN-induced GTP binding protein 1; IFIT1, IFN-induced protein with tetratricopeptide repeats 1; IFIT3, IFN-induced protein with tetratricopeptide repeats 3; IFI44, IFN-induced protein 44.IFN type II-induced genes: IDO1, indolamine-deoxygenase 1; GBP1, guanylate binding protein 1; MIG, C-X-C chemokine 9 (CXCL9); IP-10, C-X-C chemokine 10 (CXCL10); P2RY14, purinergic receptor 14.Conclusion:The present data indicate that IFN type I- and, to a lesser degree, type II-induced genes are upregulated in patients with SjS, but this phenomenon is consistently stronger in patients with systemic EGMs. In patients with only GFs IFN-induced gene upregulation is milder in PBMCs, and then probably more restricted to the exocrine target tissues.Disclosure of Interests:Nicoletta Del Papa: None declared, Claudio Vitali: None declared, Maurizio Lorini: None declared, Vincenzo Carbonelli: None declared, Wanda Maglione: None declared, Francesca Pignataro: None declared, Antonina Minniti: None declared, Nicola Montano: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UC

    Type I interferon receptor-independent and -dependent host transcriptional responses to mouse hepatitis coronavirus infection in vivo

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    <p>Abstract</p> <p>Background</p> <p>The role of type I IFNs in protecting against coronavirus (CoV) infections is not fully understood. While CoVs are poor inducers of type I IFNs in tissue culture, several studies have demonstrated the importance of the type I IFN response in controlling MHV infection in animals. The protective effectors against MHV infection are, however, still unknown.</p> <p>Results</p> <p>In order to get more insight into the antiviral gene expression induced in the brains of MHV-infected mice, we performed whole-genome expression profiling. Three different mouse strains, differing in their susceptibility to infection with MHV, were used. In BALB/c mice, which display high viral loads but are able to control the infection, 57 and 121 genes were significantly differentially expressed (≥ 1.5 fold change) upon infection at 2 and 5 days post infection, respectively. Functional association network analyses demonstrated a strong type I IFN response, with Irf1 and Irf7 as the central players. At 5 days post infection, a type II IFN response also becomes apparent. Both the type I and II IFN response, which were more pronounced in mice with a higher viral load, were not observed in 129SvEv mice, which are much less susceptible to infection with MHV. 129SvEv mice lacking the type I interferon receptor (IFNAR-/-), however, were not able to control the infection. Gene expression profiling of these mice identified type I IFN-independent responses to infection, with IFN-γ as the central player. As the BALB/c and the IFNAR-/- 129SvEv mice demonstrated very similar viral loads in their brains, we also compared their gene expression profiles upon infection with MHV in order to identify type I IFN-dependent transcriptional responses. Many known IFN-inducible genes were detected, several of which have previously been shown to play an important protective role against virus infections. We speculate that the additional type I IFN-dependent genes that we discovered may also be important for protection against MHV infection.</p> <p>Conclusion</p> <p>Transcriptional profiling of mice infected with MHV demonstrated the induction of a robust IFN response, which correlated with the viral load. Profiling of IFNAR-/- mice allowed us to identify type I IFN-independent and -dependent responses. Overall, this study broadens our present knowledge of the type I and II IFN-mediated effector responses during CoV infection <it>in vivo</it>.</p

    A Possible Anticancer Agent, Type III Interferon, Activates Cell Death Pathways and Produces Antitumor Effects

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    Recently identified interleukin-28 and -29 belong to a novel type III interferon (IFN) family, which could have distinct biological properties from type I and II IFNs. Type I IFNs, IFN-α/β, have been clinically applied for treating a certain kind of malignancies for over 30 years, but a wide range of the adverse effects hampered the further clinical applications. Type III IFNs, IFN-λs, have similar signaling pathways as IFN-α/β and inhibits proliferation of tumor cells through cell cycle arrest or apoptosis. Restricted patterns of type III IFN receptor expression in contrast to ubiquitously expressed IFN-α/β receptors suggest that type III IFNs have limited cytotoxicity to normal cells and can be a possible anticancer agent. In this paper, we summarize the current knowledge on the IFN-λs-mediated tumor cell death and discuss the functional difference between type I and III IFNs
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