A Critical Role for CCL Chemokines in the Immuno-Protection Induced by Type I Interferons and IRF8/ICSBP Against Bcr/Abl-Induced Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1001-1001
Author(s):  
Valentina Nardi ◽  
Olaia Naveiras ◽  
Mohammad Azam ◽  
George Q. Daley
Keyword(s):  
Transcriptional Profiling ◽  
Consensus Sequence ◽  
Critical Role ◽  
Myelogenous Leukemia ◽  
Type I Interferons ◽  
Leukemic Cells ◽  
Transformed Cells ◽  
Type I ◽  
Type I Ifns ◽  
Ifn Alpha

Abstract Until recently, the mainstay of Chronic Myelogenous Leukemia (CML) therapy was Interferon (IFN) alpha, which in a minority of patients induces long lasting cytogenetic remission. While the exact mechanism of action of IFN alpha in CML is still obscure, it is clear that the clinical response to IFN alpha correlates with immune system reactivity against leukemic clones. As minimal molecular disease often persists despite the use of imatinib and new Bcr-Abl inhibitors, immunotherapy remains an appealing adjunct to molecularly targeted inhibitors in CML therapy. We have shown that IRF8/ICSBP (Interferon Consensus Sequence Binding Protein) expression in Bcr-Abl transformed cells prevents their capacity to form a lethal leukemia when injected into mice, and that this protection is mediated by a long-lasting and potent CD8+ response against unknown epitopes on the leukemic cells. We hypothesized that the protection mediated by IRF8/ICSBP might be related to the anti-leukemic effects of IFN alpha. We now find that Type I IFNs like IFN alpha regulate IRF8/ICSBP expression in mouse and human cells and in Bcr-Abl transformed cells. Furthermore, type I IFNs can substitute for ICSBP in inducing the anti-leukemic immunity against Bcr-Abl transformed cells. Transcriptional profiling of cells expressing ICSBP, Bcr-Abl, or both ICSBP and Bcr-Abl identified two chemokines, CCL6 and CCL9, which were associated with the immune protection induced by IRF8/ICSBP expression. Type I IFNs and IRF8/ICSBP induce the expression of these chemokines in cells transformed with Bcr-Abl. RNAi-mediated inhibition experiments in our mouse model of CML show that these chemokines are required for the IRF8/ICSBP-mediated CD8+ anti-leukemic response to the Bcr-Abl transformed cells, suggesting that these chemokines could be exploited for immunotherapy in combination with existing Bcr-Abl peptide vaccines.

scholarly journals ICSBP-mediated immune protection against BCR-ABL–induced leukemia requires the CCL6 and CCL9 chemokines

Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3813-3820 ◽  
Author(s):  
Valentina Nardi ◽  
Olaia Naveiras ◽  
Mohammad Azam ◽  
George Q. Daley
Keyword(s):  
Murine Model ◽  
Consensus Sequence ◽  
Myelogenous Leukemia ◽  
Transformed Cells ◽  
Type I ◽  
Immune Protection ◽  
Immune Mechanism ◽  
Type I Ifns ◽  
New Strategies

Abstract Interferon (IFN) is effective at inducing complete remissions in patients with chronic myelogenous leukemia (CML), and evidence supports an immune mechanism. Here we show that the type I IFNs (alpha and beta) regulate expression of the IFN consensus sequence-binding protein (ICSBP) in BCR-ABL–transformed cells and as shown previously for ICSBP, induce a vaccine-like immunoprotective effect in a murine model of BCR-ABL–induced leukemia. We identify the chemokines CCL6 and CCL9 as genes prominently induced by the type I IFNs and ICSBP, and demonstrate that these immunomodulators are required for the immunoprotective effect of ICSBP expression. Insights into the role of these chemokines in the antileukemic response of IFNs suggest new strategies for immunotherapy of CML.

scholarly journals Activation of Stimulator of Interferon Genes (STING) and Sjögren Syndrome

2018 ◽  
Vol 97 (8) ◽  
pp. 893-900 ◽  
Author(s):  
J. Papinska ◽  
H. Bagavant ◽  
G.B. Gmyrek ◽  
M. Sroka ◽  
S. Tummala ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Infections ◽  
Critical Role ◽  
Autoimmune Disorder ◽  
Sjögren Syndrome ◽  
Lymphoid Cells ◽  
Type I Interferons ◽  
Sjogren Syndrome ◽  
Type I ◽  
Type I Ifns

Sjögren syndrome (SS), a chronic autoimmune disorder causing dry mouth, adversely affects the overall oral health in patients. Activation of innate immune responses and excessive production of type I interferons (IFNs) play a critical role in the pathogenesis of this disorder. Recognition of nucleic acids by cytosolic nucleic acid sensors is a major trigger for the induction of type I IFNs. Upon activation, cytosolic DNA sensors can interact with the stimulator of interferon genes (STING) protein, and activation of STING causes increased expression of type I IFNs. The role of STING activation in SS is not known. In this study, to investigate whether the cytosolic DNA sensing pathway influences SS development, female C57BL/6 mice were injected with a STING agonist, dimethylxanthenone-4-acetic acid (DMXAA). Salivary glands (SGs) were studied for gene expression and inflammatory cell infiltration. SG function was evaluated by measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and autoantibodies. Primary SG cells were used to study the expression and activation of STING. Our data show that systemic DMXAA treatment rapidly induced the expression of Ifnb1, Il6, and Tnfa in the SGs, and these cytokines were also elevated in circulation. In contrast, increased Ifng gene expression was dominantly detected in the SGs. The type I innate lymphoid cells present within the SGs were the major source of IFN-γ, and their numbers increased significantly within 3 d of treatment. STING expression in SGs was mainly observed in ductal and interstitial cells. In primary SG cells, DMXAA activated STING and induced IFN-β production. The DMXAA-treated mice developed autoantibodies, sialoadenitis, and glandular hypofunction. Our study demonstrates that activation of the STING pathway holds the potential to initiate SS. Thus, apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should also be considered as possible triggers for SS.

Immune-Mediated Protection Against BCR/ABL-Induced Leukemia: A Common Pathway Shared between IRF8/ICSBP and IFN alpha and beta.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2872-2872
Author(s):  
Valentina Nardi ◽  
Azam Mohammed ◽  
George Q. Daley
Keyword(s):  
Immune Response ◽  
Alternative Hypothesis ◽  
Consensus Sequence ◽  
Ectopic Expression ◽  
Leukemic Cells ◽  
Transformed Cells ◽  
Common Pathway ◽  
Ifn Alpha ◽  
Immune Mediated

Abstract Most Chronic Myeloid Leukemia (CML) patients are treated with the targeted agent imatinib (Gleevec), but cytogenetic remission is rarely achieved and the only cure remains bone marrow transplantation. The mainstay of therapy prior to imatinib was interferon (IFN) alpha, which induces cytogenic remission in a minority of patients. Because clinical response to IFN alpha correlates with immune system reactivity against leukemic clones, immunotherapy may be an important adjunct to imatinib. ICSBP (Interferon Consensus Sequence Binding Protein) is a tumor suppressor of CML. Ectopic expression of ICSBP in Bcr-Abl transformed cells prevents the formation of a lethal leukemia, and we have shown that this anti-leukemic effect is mediated by a long-lasting and potent CD8+ response against unknown epitopes on the leukemic cells. We have begun to characterize the immune response against CML induced by ICSBP and to understand its relationship to the anti-leukemic effects of IFN alpha. IFN alpha and IFN beta can substitute for ICSBP expression in inducing potent anti-leukemic immunity against BCR-ABL transformed cells. We could find little evidence for the direct regulation of the IFN genes by ICSBP; thus we have favored the alternative hypothesis that ICSBP and IFNs alpha and beta activate a common pathway that ultimately triggers an immune-mediated anti-leukemic response. To test this hypothesis, we compared the transcriptional profiles of BaF3 cells to those overexpressing Bcr-Abl, ICSBP, or both (unpublished data). Our data confirm the reported effects of ICSBP on genes that regulate proliferation and apoptosis in cells overexpressing Bcr-Abl (e.g. cyclin D2). In addition, our analysis revealed an interesting new mechanism through which ICSBP may stimulate an anti-leukemic immune response and Bcr-Abl expressing cells may escape immune detection. IFN alpha and beta appear to share the mechanism induced by ICSBP. Our data confirm the differential expression of several known (e.g. Proteinase 3) as well as new potential protein epitopes of the anti-leukemic immune response induced by ICSBP and the IFNs. Our in vivo experiments should shed further light on the role of the immune regulatory genes we have identified in the immune response to CML.

scholarly journals AB0042 CYTOKINE NETWORK ELUCIDATED BY THE QUANTIFICATION OF MULTIPLE CYTOKINES IN THE SERUM SEQUENTIALLY SAMPLED FROM RA PATIENTS WHO WERE TREATED WITH BIOLOGIC DMARDS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1323.2-1324
Author(s):  
K. Sato ◽  
S. Mamada ◽  
C. Hayashi ◽  
T. Nagashima ◽  
S. Minota
Keyword(s):  
Bone Erosion ◽  
Feedback System ◽  
Serum Levels ◽  
Type I Interferons ◽  
Type I ◽  
Serum Samples ◽  
Cytokine Network ◽  
Biologic Dmards ◽  
Type I Ifns ◽  
Before And After

Background:Biologic disease modifying anti-rheumatic drugs (DMARDs) have demonstrated that proinflammatory cytokines such as interleukin (IL-) 6 and tumor necrosis factor (TNF) play important roles in the pathogenesis of rheumatoid arthritis (RA). Other cytokines, such as type I interferons (IFNs), are also implicated in its pathogenesis (ref 1). However, the complete picture of the cytokine network involved in RA remains to be elucidated.Objectives:By quantifying sets of cytokines in the serum of RA patients before and after treatment with various biologic DMARDs, we sought to determine the effects of drugs on (A) type I IFNs, (B) soluble IL-6 receptors, and (C) other cytokines.Methods:52 patients with RA were treated with various biologic DMARDs (tocilizumab (TOC): 16, abatacept (ABT): 15, and TNF inhibitors (TNFi): 21). Serum samples were obtained (1) before, (2) approximately 4 weeks after (3) and approximately 12 weeks after the initiation of treatment. A suspension bead-array system was used for analysis; Bio-Plex Human Cytokine 17-plex Assay kits and Express Custom Panels (Bio-Rad), including IFN-β, IFN-α2, soluble IL-6 receptor α (sIL6Rα) and gp130 were used.Results:(1) As expected, the disease activity score 28-joiny count (DAS28) using the erythrocyte sedimentation rate (ESR) significantly decreased in all three groups (TOC, ABT and TNFi) by 12 weeks.(2) IFN-α2 was barely detected in the serum samples. IFN-β seemed to increase slightly in the ABT group, but the increase was not statistically significant.(3) The levels of sIL6Rα did not change substantially. Those of gp130 decreased slightly but significantly in the TOC group by 12 weeks.(4) The levels of IL-6 decreased significantly in the ABT group by 12 weeks. Those in the TNFi group decreased significantly at 4 weeks but not 12 weeks (Fig. 1A).(5) The levels of IL-7 decreased significantly only in the TOC group (Fig. 1B).Conclusion:(1) The biologic DMARDs tested in this study did not significantly affect the serum levels of type I IFNs in this study.(2) The decrease in gp130 in the TOC group may imply that gp130 is induced by IL-6, although whether this level of decrease has physiological significance is open to question.(3) Serum IL-6 was significantly decreased in the TNFi group at 4 weeks but not 12 weeks. TNF has been reported to induce IL-6 (ref 2), but negative feedback loop(s) may be present. Such a feedback system might make the discontinuation of TNFi difficult, even if patients are in remission.(4) IL-7 may be a target of IL-6. A higher level of IL-7 has been reported to be present in the joints of RA patients compared with osteoarthrosis and it is a cytokine implicated in the differentiation of osteoclasts (ref 3). This may partly explain the effect of TOC on preventing bone erosion in RA.References:[1]Ann Rheum Dis. 2007; 66: 1008–14[2]Rheumatology 2007; 46: 920-6[3]Rheumatology 2008; 47: 753-9Acknowledgments:We thank all the members of the Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University. We are also grateful to the patients involved in this study.Disclosure of Interests:Kojiro Sato Grant/research support from: Abbie, Pfizer, Chugai, Astellas, Mitsubishi-Tanabe, Ono, Takeda, Sachiko Mamada: None declared, Chiyomi Hayashi: None declared, Takao Nagashima: None declared, Seiji Minota: None declared

scholarly journals Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

2019 ◽  
Author(s):  
Paulino Barragan-Iglesias ◽  
Úrzula Franco-Enzástiga ◽  
Vivekanand Jeevakumar ◽  
Andi Wangzhou ◽  
Vinicio Granados-Soto ◽  
...  
Keyword(s):  
Viral Infection ◽  
Viral Infections ◽  
Mrna Translation ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Drg Neurons ◽  
Pain Hypersensitivity ◽  
Type I Ifns ◽  
Pain Sensitization

ABSTRACTOne of the first signs of viral infection is body-wide aches and pain. While this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization are well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I interferons stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENTIt is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. While specific mechanisms have been discovered for diverse bacteria and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type 1 interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling) that is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

Adjuvant activity of type I interferons

2008 ◽  
Vol 389 (5) ◽  
Author(s):  
Michael G. Tovey ◽  
Christophe Lallemand ◽  
George Thyphronitis
Keyword(s):  
Immune Response ◽  
Antibody Response ◽  
Antigen Presentation ◽  
Response Characteristic ◽  
Influenza Virus Vaccine ◽  
Type I Interferons ◽  
Type I ◽  
Adjuvant Activity ◽  
Virus Challenge ◽  
Type I Ifns

AbstractType I interferons (IFNs) produced primarily by plasmacytoid dendritic cells (pDCs) as part of the innate immune response to infectious agents induce the maturation of myeloid DCs and enhance antigen presentation. Type I IFNs also enhance apoptosis of virus-infected cells, stimulate cross priming and enhanced presentation of viral peptides. Type I IFNs are powerful polyclonal B-cell activators that induce a strong primary humoral immune response characterized by isotype switching and protection against virus challenge. Type I IFNs stimulate an IgG2a antibody response characteristic of Th1 immunity when ad-mixed with influenza virus vaccine and injected intramuscurarly (i.m.) or administered intranasally. The adjuvant activity of type I IFNs has been shown to involve direct effects of IFN on B-cells, effects on T-cells, as well as effects on antigen presentation. Oromucosal administration of type I IFNs concomitantly with i.m. injection of vaccine alone can also enhance the antibody response to influenza vaccination by enhancing trafficking of antigen-presenting cells towards the site of vaccination. Recombinant IFNs are potent adjuvants that may find application in both parenterally and mucosally administered vaccines.

scholarly journals Thioredoxin 2 Negatively Regulates Innate Immunity to RNA Viruses by Disrupting the Assembly of the Virus-Induced Signaling Adaptor Complex

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Dan Li ◽  
Wenping Yang ◽  
Yi Ru ◽  
Jingjing Ren ◽  
Xiangtao Liu ◽  
...  
Keyword(s):  
Complex Formation ◽  
Rna Viruses ◽  
Critical Role ◽  
Type I Interferons ◽  
Type I ◽  
Host Proteins ◽  
Innate Antiviral Response ◽  
Thioredoxin 2

ABSTRACT The virus-induced signaling adaptor (VISA) complex plays a critical role in the innate immune response to RNA viruses. However, the mechanism of VISA complex formation remains unclear. Here, we demonstrate that thioredoxin 2 (TRX2) interacts with VISA at mitochondria both in vivo and in vitro. Knockdown and knockout of TRX2 enhanced the formation of the VISA-associated complex, as well as virus-triggered activation of interferon regulatory factor 3 (IRF3) and transcription of the interferon beta 1 (IFNB1) gene. TRX2 inhibits the formation of VISA aggregates by repressing reactive oxygen species (ROS) production, thereby disrupting the assembly of the VISA complex. Furthermore, our data suggest that the C93 residue of TRX2 is essential for inhibition of VISA aggregation, whereas the C283 residue of VISA is required for VISA aggregation. Collectively, these findings uncover a novel mechanism of TRX2 that negatively regulates VISA complex formation. IMPORTANCE The VISA-associated complex plays pivotal roles in inducing type I interferons (IFNs) and eliciting the innate antiviral response. Many host proteins are identified as VISA-associated-complex proteins, but how VISA complex formation is regulated by host proteins remains enigmatic. We identified the TRX2 protein as an important regulator of VISA complex formation. Knockout of TRX2 increases virus- or poly(I·C)-triggered induction of type I IFNs at the VISA level. Mechanistically, TRX2 inhibits the production of ROS at its C93 site, which impairs VISA aggregates at its C283 site, and subsequently impedes the assembly of the VISA complex. Our findings suggest that TRX2 plays an important role in the regulation of VISA complex assembly.

Differential expression and activity of the porcine type I interferon family

2010 ◽  
Vol 42 (2) ◽  
pp. 248-258 ◽  
Author(s):  
Yongming Sang ◽  
Raymond R. R. Rowland ◽  
Richard A. Hesse ◽  
Frank Blecha
Keyword(s):  
Antiviral Activity ◽  
Expression Profiles ◽  
Type I Interferons ◽  
Respiratory Syndrome Virus ◽  
Target Cells ◽  
Type I ◽  
Antiviral Responses ◽  
Type I Ifns ◽  
Antiviral Activities ◽  
Vesicular Stomatitis

Type I interferons (IFNs) are central to innate and adaptive immunity, and many have unique developmental and physiological functions. However, in most species, only two subtypes, IFN-α and IFN-β, have been well studied. Because of the increasing importance of zoonotic viral diseases and the use of pigs to address human research questions, it is important to know the complete repertoire and activity of porcine type I IFNs. Here we show that porcine type I IFNs comprise at least 39 functional genes distributed along draft genomic sequences of chromosomes 1 and 10. These functional IFN genes are classified into 17 IFN-α subtypes, 11 IFN-δ subtypes, 7 IFN-ω subtypes, and single-subtype subclasses of IFN-αω, IFN-β, IFN-ε, and IFN-κ. We found that porcine type I IFNs have diverse expression profiles and antiviral activities against porcine reproductive and respiratory syndrome virus (PRRSV) and vesicular stomatitis virus (VSV), with activity ranging from 0 to >105 U·ng−1·ml−1. Whereas most IFN-α subtypes retained the greatest antiviral activity against both PRRSV and VSV in porcine and MARC-145 cells, some IFN-δ and IFN-ω subtypes, IFN-β, and IFN-αω differed in their antiviral activity based on target cells and viruses. Several IFNs, including IFN-α7/11, IFN-δ2/7, and IFN-ω4, exhibited minimal or no antiviral activity in the tested target cell-virus systems. Thus comparative studies showed that antiviral activity of porcine type I IFNs is virus- and cell-dependent, and IFN-αs are positively correlated with induction of MxA, an IFN-stimulated gene. Collectively, these data provide fundamental genomic information for porcine type I IFNs, information that is necessary for understanding porcine physiological and antiviral responses.

Type I interferons induce peripheral T regulatory cell differentiation under tolerogenic conditions

2020 ◽  
Author(s):  
Sara Vitale ◽  
Valentina Russo ◽  
Beatrice Dettori ◽  
Cecilia Palombi ◽  
Denis Baev ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Dominant Role ◽  
Critical Role ◽  
Peripheral Tolerance ◽  
Type I Interferons ◽  
Type I ◽  
T Regulatory Cell ◽  
Cell Conversion

Abstract The type I interferons are central to a vast array of immunological functions. The production of these immune-modulatory molecules is initiated at the early stages of the innate immune responses and, therefore, plays a dominant role in shaping downstream events in both innate and adaptive immunity. Indeed, the major role of IFN-α/β is the induction of priming states, relevant for the functional differentiation of T lymphocyte subsets. Among T-cell subtypes, the CD4+CD25+Foxp3+ T regulatory cells (Tregs) represent a specialized subset of CD4+ T cells with a critical role in maintaining peripheral tolerance and immune homeostasis. Although the role of type I interferons in maintaining the function of thymus-derived Tregs has been previously described, the direct contribution of these innate factors to peripheral Treg (pTreg) and induced Treg (iTreg) differentiation and suppressive function is still unclear. We now show that, under tolerogenic conditions, IFN-α/β play a critical role in antigen-specific and also polyclonal naive CD4+ T-cell conversion into peripheral antigen-specific CD4+CD25+Foxp3+ Tregs and inhibit CD4+ T helper (Th) cell expansion in mice. While type I interferons sustain the expression and the activation of the transcription master regulators Foxp3, Stat3 and Stat5, these innate molecules reciprocally inhibit Th17 cell differentiation. Altogether, these results indicate a new pivotal role of IFN-α/β on pTreg differentiation and induction of peripheral tolerance, which may have important implications in the therapeutic control of inflammatory disorders, such as of autoimmune diseases.

scholarly journals Context Is Key: Delineating the Unique Functions of IFNα and IFNβ in Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Lindsey E. Fox ◽  
Marissa C. Locke ◽  
Deborah J. Lenschow
Keyword(s):  
Viral Infections ◽  
Biological Activities ◽  
Type I Interferons ◽  
Type I ◽  
Disease States ◽  
Type I Ifns ◽  
Wide Range ◽  
Individual Type ◽  
Effector Cytokines ◽  
The Individual

Type I interferons (IFNs) are critical effector cytokines of the immune system and were originally known for their important role in protecting against viral infections; however, they have more recently been shown to play protective or detrimental roles in many disease states. Type I IFNs consist of IFNα, IFNβ, IFNϵ, IFNκ, IFNω, and a few others, and they all signal through a shared receptor to exert a wide range of biological activities, including antiviral, antiproliferative, proapoptotic, and immunomodulatory effects. Though the individual type I IFN subtypes possess overlapping functions, there is growing appreciation that they also have unique properties. In this review, we summarize some of the mechanisms underlying differential expression of and signaling by type I IFNs, and we discuss examples of differential functions of IFNα and IFNβ in models of infectious disease, cancer, and autoimmunity.

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