Interferon (IFN)
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Induction of a TRAIL Mediated Suicide Program by Interferon Alpha in Primary E€Usion Lymphoma
Oncogene (2001) 20, 7029 ± 7040 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Induction of a TRAIL mediated suicide program by interferon alpha in primary eusion lymphoma Ngoc L Toomey1,4, Vadim V Deyev2,4, Charles Wood3, Lawrence H Boise2, Duncan Scott1, Lei Hua Liu1, Lisa Cabral1, Eckhard R Podack2, Glen N Barber2 and William J Harrington Jr*,1 1Department of Medicine University of Miami School of Medicine, Miami, Florida, FL 33136, USA; 2Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida, FL 33136, USA; 3School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, NE 68588, USA Gammaherpes viruses are often detected in lymphomas Virus (EBV) or Human Herpes Virus Type 8 (HHV-8) arising in immunocompromised patients. We have found have been isolated from lymphomas found in im- that Azidothymidine (AZT) alone induces apoptosis in munosuppressed organ transplant recipients, children Epstein Barr Virus (EBV) positive Burkitt's lymphoma with hereditary immunode®ciencies and patients with (BL) cells but requires interferon alpha (IFN-a) to induce acquired immunode®ciency (AIDS) (Swinnen, 1999; apoptosis in Human Herpes Virus Type 8 (HHV-8) Goldsby and Carroll, 1998; Knowles, 1999). Many of positive Primary Eusion Lymphomas (PEL). Our these tumors can be categorized into distinct subtypes analysis of a series of AIDS lymphomas revealed that based on a variety of morphologic and molecular IFN-a selectively induced very high levels of the Death criteria. For example, AIDS associated large cell Receptor (DR) tumor necrosis factor-related apoptosis- diuse or immunoblastic lymphomas (DLCL, IBL) inducing ligand (TRAIL) in HHV-8 positive PEL lines are often EBV positive while AIDS associated Burkitt's and primary tumor cells whereas little or no induction lymphomas (BL) less frequently contain EBV (Gaidano was observed in primary EBV+ AIDS lymphomas and et al., 1994). -
CIITA Stimulation of Transcription Factor Binding to Major Histocompatibility Complex Class II and Associated Promoters in Vivo
Proc. Natl. Acad. Sci. USA Vol. 95, pp. 6267–6272, May 1998 Genetics CIITA stimulation of transcription factor binding to major histocompatibility complex class II and associated promoters in vivo i KENNETH L. WRIGHT*†§,KEH-CHUANG CHIN‡§¶,MICHAEL LINHOFF*, CHERYL SKINNER*, JEFFREY A. BROWN , i JEREMY M. BOSS ,GEORGE R. STARK**, AND JENNY P.-Y. TING*†† *Lineberger Comprehensive Cancer Center and the Department of Immunology and Microbiology, and ‡Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599; iDepartment of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; and **Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195 Contributed by George R. Stark, March 12, 1998 ABSTRACT CIITA is a master transactivator of the ma- RFX5 (14). However, the mode of action of CIITA and its in jor histocompatibility complex class II genes, which are vivo target have remained elusive. involved in antigen presentation. Defects in CIITA result in Changes in promoter assembly or proteinyDNA interactions fatal immunodeficiencies. CIITA activation is also the control can be detected in intact cells by in vivo genomic footprinting point for the induction of major histocompatibility complex (15). Analysis of the DRA promoter by this technique has class II and associated genes by interferon-g, but CIITA does revealed interactions at promoter-proximal transcription fac- not bind directly to DNA. Expression of CIITA in G3A cells, tor binding sites X and Y in both B lymphocytes and IFN-g- which lack endogenous CIITA, followed by in vivo genomic treated cells (16, 17). The Ii and DMB promoters show similar footprinting, now reveals that CIITA is required for the interactions at the their X and Y sites (18–20). -
Porvac® Subunit Vaccine E2-CD154 Induces Remarkable Rapid Protection Against Classical Swine Fever Virus
Article Porvac® Subunit Vaccine E2-CD154 Induces Remarkable Rapid Protection against Classical Swine Fever Virus Yusmel Sordo-Puga 1, Marisela Suárez-Pedroso 1 , Paula Naranjo-Valdéz 2, Danny Pérez-Pérez 1, Elaine Santana-Rodríguez 1, Talia Sardinas-Gonzalez 1, Mary Karla Mendez-Orta 1, Carlos A. Duarte-Cano 1, Mario Pablo Estrada-Garcia 1 and María Pilar Rodríguez-Moltó 1,* 1 Animal Biotechnology Department, Center for Genetic Engineering and Biotechnology, P.O. Box 6162, Havana 10600, Cuba; [email protected] (Y.S.-P.); [email protected] (M.S.-P.); [email protected] (D.P.-P.); [email protected] (E.S.-R.); [email protected] (T.S.-G.); [email protected] (M.K.M.O.); [email protected] (C.A.D.); [email protected] (M.P.E.) 2 Central Laboratory Unit for Animal Health (ULCSA), Havana 11400, Cuba; [email protected] * Correspondence: [email protected]; Tel.: +53-7-2504419 Abstract: Live attenuated C-strain classical swine fever vaccines provide early onset protection. These vaccines confer effective protection against the disease at 5–7 days post-vaccination. It was previously reported that intramuscular administration of the Porvac® vaccine protects against highly virulent Citation: Sordo-Puga, Y.; classical swine fever virus (CSFV) “Margarita” strain as early as seven days post-vaccination. In Suárez-Pedroso, M.; Naranjo-Valdéz, order to identify how rapidly protection against CSFV is conferred after a single dose of the Porvac® P.; Pérez-Pérez, D.; subunit vaccine E2-CD154, 15 swine, vaccinated with a single dose of Porvac®, were challenged Santana-Rodríguez, E.; 3 intranasally at five, three, and one day post-vaccination with 2 × 10 LD50 of the highly pathogenic Sardinas-Gonzalez, T.; Mendez-Orta, Cuban “Margarita” strain of the classical swine fever virus. -
Significant Shortest Paths for the Detection of Putative Disease Modules
bioRxiv preprint doi: https://doi.org/10.1101/2020.04.01.019844; this version posted April 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. SIGNIFICANT SHORTEST PATHS FOR THE DETECTION OF PUTATIVE DISEASE MODULES Daniele Pepe1 1Department of Oncology, KU Leuven, LKI–Leuven Cancer Institute, Leuven, Belgium Email address: DP: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.04.01.019844; this version posted April 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Keywords Structural equation modeling, significant shortest paths, pathway analysis, disease modules. Abstract Background The characterization of diseases in terms of perturbated gene modules was recently introduced for the analysis of gene expression data. Some approaches were proposed in literature, but many times they are inductive approaches. This means that starting directly from data, they try to infer key gene networks potentially associated to the biological phenomenon studied. However they ignore the biological information already available to characterize the gene modules. Here we propose the detection of perturbed gene modules using the combination of data driven and hypothesis-driven approaches relying on biological metabolic pathways and significant shortest paths tested by structural equation modeling. -
Age- and Gender-Specific Modulation of Serum Osteopontin and Interferon-Α by Osteopontin Genotype in Systemic Lupus Er
Genes and Immunity (2009) 10, 487–494 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene ORIGINAL ARTICLE Age- and gender-specific modulation of serum osteopontin and interferon-a by osteopontin genotype in systemic lupus erythematosus SN Kariuki1, JG Moore1, KA Kirou2,MKCrow2, TO Utset1 and TB Niewold1 1Section of Rheumatology, University of Chicago, Chicago, IL, USA and 2Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, NY, USA Osteopontin (OPN) is a multifunctional cytokine involved in long bone remodeling and immune system signaling. Additionally, OPN is critical for interferon-a (IFN-a) production in murine plasmacytoid dendritic cells. We have previously shown that IFN-a is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variants of OPN have been associated with SLE susceptibility, and one study suggests that this association is particular to men. In this study, the 3 0 UTR SLE-risk variant of OPN (rs9138C) was associated with higher serum OPN and IFN-a in men (P ¼ 0.0062 and P ¼ 0.0087, respectively). In women, the association between rs9138 C and higher serum OPN and IFN-a was restricted to younger subjects, and risk allele carriers showed a strong age-related genetic effect of rs9138 genotype on both serum OPN and IFN-a (Po0.0001). In African- American subjects, the 5 0 region single nucleotide polymorphisms, rs11730582 and rs28357094, were associated with anti- RNP antibodies (odds ratio (OR) ¼ 2.9, P ¼ 0.0038 and OR ¼ 3.9, P ¼ 0.021, respectively). Thus, we demonstrate two distinct genetic influences of OPN on serum protein traits in SLE patients, which correspond to previously reported SLE-risk variants. -
Interferon-Γ Enhances Interleukin 12 Production in Rheumatoid Synovial
Interferon-γ Enhances Interleukin 12 Production in Rheumatoid Synovial Cells via CD40-CD154 Dependent and Independent Pathways MINETAKE KITAGAWA, HIROSHI SUZUKI, YOSHIHIRO ADACHI, HIROSHI NAKAMURA, SHINICHI YOSHINO, and TAKAYUKI SUMIDA ABSTRACT. Objective. To determine the role of interferon-γ (IFN-γ) in CD40-CD154 dependent production of interleukin 12 (IL-12) by synovial cells of patients with rheumatoid arthritis (RA). Methods. We examined the effects of IFN-γ, tumor necrosis factor-α (TNF-α), and granulocyte- macrophage colony stimulating factor (GM-CSF) on CD40 expression on CD68+ synovial macrophage-lineage cells (SMC). The effects of IFN-γ and soluble CD154 (sCD154) on IL-12 production by RA synovial cells were determined by ELISA. Results. CD68+ SMC expressed substantial levels of CD40. IFN-γ, but not TNF-α or GM-CSF, markedly upregulated CD40 expression on CD68+ SMC. IFN-γ also dose dependently increased IL- γ 12 production by synovial cells. The effects of IFN- on CD40 expression (EC50 = 127.4 U/ml) were observed at a concentration 19 times lower than the effects on IL-12 production (EC50 = 6.8 U/ml). Treatment with IFN-γ at a concentration low enough to augment CD40 expression but not IL-12 production enhanced spontaneous IL-12 production synergy with sCD154. The synergistic enhance- ment of spontaneous IL-12 production was abrogated by CD40-Fc. In contrast, IL-12 production induced by high concentration of IFN-γ was not neutralized by CD40-Fc. Conclusion. IFN-γ enhanced IL-12 production via both CD40-CD154 dependent and independent pathways in RA synovium. IFN-γ may play a crucial role in the development of RA synovitis through regulation of IL-12 production. -
Dysregulated Interferon Response Underlying Severe COVID-19
viruses Review Dysregulated Interferon Response Underlying Severe COVID-19 LeAnn Lopez y, Peter C. Sang y, Yun Tian y and Yongming Sang * Department of Agricultural and Environmental Sciences, College of Agriculture, Tennessee State University, 3500 John A. Merritt Boulevard, Nashville, TN 37209, USA; [email protected] (L.L.); [email protected] (P.C.S.); [email protected] (Y.T.) * Correspondence: [email protected]; Tel.: +1-615-963-5183 These authors contributed equally. y Academic Editor: Andrew Davidson Received: 27 October 2020; Accepted: 9 December 2020; Published: 13 December 2020 Abstract: Innate immune interferons (IFNs), including type I and III IFNs, constitute critical antiviral mechanisms. Recent studies reveal that IFN dysregulation is key to determine COVID-19 pathogenesis. Effective IFN stimulation or prophylactic administration of IFNs at the early stage prior to severe COVID-19 may elicit an autonomous antiviral state, restrict the virus infection, and prevent COVID-19 progression. Inborn genetic flaws and autoreactive antibodies that block IFN response have been significantly associated with about 14% of patients with life-threatening COVID-19 pneumonia. In most severe COVID-19 patients without genetic errors in IFN-relevant gene loci, IFN dysregulation is progressively worsened and associated with the situation of pro-inflammation and immunopathy, which is prone to autoimmunity. In addition, the high correlation of severe COVID-19 with seniority, males, and individuals with pre-existing comorbidities will be plausibly explained by the coincidence of IFN aberrance in these situations. Collectively, current studies call for a better understanding of the IFN response regarding the spatiotemporal determination and subtype-specificity against SARS-CoV-2 infections, which are warranted to devise IFN-related prophylactics and therapies. -
ATP-Binding and Hydrolysis in Inflammasome Activation
molecules Review ATP-Binding and Hydrolysis in Inflammasome Activation Christina F. Sandall, Bjoern K. Ziehr and Justin A. MacDonald * Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada; [email protected] (C.F.S.); [email protected] (B.K.Z.) * Correspondence: [email protected]; Tel.: +1-403-210-8433 Academic Editor: Massimo Bertinaria Received: 15 September 2020; Accepted: 3 October 2020; Published: 7 October 2020 Abstract: The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure. -
Pegasys, INN-Peginterferon Alfa-2A
SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion and scientific discussion on procedures, which have been finalised before 1 April 2005. For scientific information on procedures after this date please refer to module 8B. 1. Introduction Peginterferon alfa-2a is a polyethylene glycol (PEG)-modified form of human recombinant interferon alfa-2a intended for the treatment of adult patients with chronic hepatitis C (CHC) or chronic hepatitis B (CHB). Chronic hepatitis C is a major public health problem: hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease, accounting for 70% of cases of chronic hepatitis in industrialised countries. Globally there are an estimated 150 million chronic carriers of the virus, including 5 million in Western Europe. Without treatment approximately 30% of those infected with HCV will develop cirrhosis over a time frame of 30 years or more. For those with HCV-related cirrhosis, the prognosis is poor – a significant proportion will develop a life-threatening complication (either decompensated liver disease or an hepatocellular carcinoma) within a few years. The only therapy for those with advanced cirrhosis is liver transplantation, which carries a high mortality. In those who survive transplantation, viral recurrence in the new liver is almost inevitable and a significant proportion of infected liver grafts develop a progressive fibrosis that leads to recurrence of cirrhosis within 5 years. Interferon alfa monotherapy has been shown to be effective for the treatment of chronic hepatitis although sustained response rates occurred in approximately 15 to 30 % of patients treated for long duration (12-18 months). The current reference therapy is interferon alpha in combination with ribavirin, which resulted in an increase in biochemical and virological sustained response rates to approximately 40 % in naïve patients. -
A Role for the Nlr Family Members Nlrc4 and Nlrp3 in Astrocytic Inflammasome Activation and Astrogliosis
A ROLE FOR THE NLR FAMILY MEMBERS NLRC4 AND NLRP3 IN ASTROCYTIC INFLAMMASOME ACTIVATION AND ASTROGLIOSIS Leslie C. Freeman A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics and Molecular Biology. Chapel Hill 2016 Approved by: Jenny P. Y. Ting Glenn K. Matsushima Beverly H. Koller Silva S. Markovic-Plese Pauline. Kay Lund ©2016 Leslie C. Freeman ALL RIGHTS RESERVED ii ABSTRACT Leslie C. Freeman: A Role for the NLR Family Members NLRC4 and NLRP3 in Astrocytic Inflammasome Activation and Astrogliosis (Under the direction of Jenny P.Y. Ting) The inflammasome is implicated in many inflammatory diseases but has been primarily studied in the macrophage-myeloid lineage. Here we demonstrate a physiologic role for nucleotide-binding domain, leucine-rich repeat, CARD domain containing 4 (NLRC4) in brain astrocytes. NLRC4 has been primarily studied in the context of gram-negative bacteria, where it is required for the maturation of pro-caspase-1 to active caspase-1. We show the heightened expression of NLRC4 protein in astrocytes in a cuprizone model of neuroinflammation and demyelination as well as human multiple sclerotic brains. Similar to macrophages, NLRC4 in astrocytes is required for inflammasome activation by its known agonist, flagellin. However, NLRC4 in astrocytes also mediate inflammasome activation in response to lysophosphatidylcholine (LPC), an inflammatory molecule associated with neurologic disorders. In addition to NLRC4, astrocytic NLRP3 is required for inflammasome activation by LPC. Two biochemical assays show the interaction of NLRC4 with NLRP3, suggesting the possibility of a NLRC4-NLRP3 co-inflammasome. -
The RFX Complex Is Crucial for the Constitutive and CIITA-Mediated Transactivation of MHC Class I and 2-Microglobulin Genes
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Immunity, Vol. 9, 531±541, October, 1998, Copyright 1998 by Cell Press The RFX Complex Is Crucial for the Constitutive and CIITA-Mediated Transactivation of MHC Class I and b2-Microglobulin Genes Sam J. P. Gobin,² Ad Peijnenburg,² of the NF-kB/Rel family and are thought to be essential Marja van Eggermond, Marlijn van Zutphen, for both constitutive and cytokine-induced expression Rian van den Berg, and Peter J. van den Elsen* (Girdlestone et al., 1993; Mansky et al., 1994). The ISRE Department of Immunohematology and Blood Bank is bound by factors of the interferon regulatory factor Leiden University Medical Center (IRF) family and mediates the induction of MHC class I 2333 ZA Leiden expression by interferons (Girdlestone et al., 1993). Site The Netherlands a was originally described as being important for the constitutive expression of MHC class I genes (Dey et al., 1992). However, a crucial role in a novel route of Summary HLA class I gene activation mediated by the class II transactivator (CIITA) has recently been attributed to In type III bare lymphocyte syndrome (BLS) patients, site a (Gobin et al., 1997; Martin et al., 1997). Enhancer defects in the RFX protein complex result in a lack of B contains an inverted CCAAT box sequence that plays MHC class II and reduced MHC class I cell surface a role in basal MHC class I gene transcription (Schoneich et al., 1997). In the promoter region of the m gene, expression. -
Genomic Analyses of PMBL Reveal New Drivers and Mechanisms of Sensitivity to PD-1 Blockade
Regular Article LYMPHOID NEOPLASIA Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade Bjoern Chapuy,1,2,* Chip Stewart,3,* Andrew J. Dunford,3,* Jaegil Kim,3 Kirsty Wienand,1 Atanas Kamburov,3 Gabriel K. Griffin,4 Pei-Hsuan Chen,4 Ana Lako,4 Robert A. Redd,5 Claire M. Cote,1 Matthew D. Ducar,6 Aaron R. Thorner,6 Scott J. Rodig,4 Gad Getz,3,7,8,† Downloaded from https://ashpublications.org/blood/article-pdf/134/26/2369/1549702/bloodbld2019002067.pdf by Margaret Shipp on 30 December 2019 and Margaret A. Shipp1,† 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 2Department of Hematology and Oncology, University Medical Center Gottingen,¨ Gottingen,¨ Germany; 3Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; 4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 5Department of Data Sciences and 6Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA; and 7Department of Pathology and 8Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA KEY POINTS Primary mediastinal large B-cell lymphomas (PMBLs) are aggressive tumors that typically present as large mediastinal masses in young women. PMBLs share clinical, transcriptional, l Comprehensive genomic analyses of and molecular features with classical Hodgkin lymphoma (cHL), including constitutive PMBL reveal new activation of nuclear factor kB (NF-kB), JAK/STAT signaling, and programmed cell death genetic drivers such protein 1 (PD-1)–mediated immune evasion. The demonstrated efficacy of PD-1 blockade in as ZNF217. relapsed/refractory PMBLs led to recent approval by the US Food and Drug Administration l High mutational and underscored the importance of characterizing targetable genetic vulnerabilities in this burden, MSI, and disease.