DOCSLIB.ORG

Activation of Th1 Lymphocytes Monocyte Stabilin-1 Suppresses

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Activation of Th1 Lymphocytes Monocyte Stabilin-1 Suppresses Monocyte Stabilin-1 Suppresses the Activation of Th1 Lymphocytes Senthil Palani, Kati Elima, Eeva Ekholm, Sirpa Jalkanen and Marko Salmi This information is current as of October 1, 2021. J Immunol published online 25 November 2015 http://www.jimmunol.org/content/early/2015/11/25/jimmun ol.1500257 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2015/11/25/jimmunol.150025 Material 7.DCSupplemental Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 25, 2015, doi:10.4049/jimmunol.1500257 The Journal of Immunology Monocyte Stabilin-1 Suppresses the Activation of Th1 Lymphocytes Senthil Palani,*,†,‡ Kati Elima,*,x Eeva Ekholm,{ Sirpa Jalkanen,*,‖ and Marko Salmi*,‖ In this study, we analyzed the putative functions of stabilin-1 in blood monocytes. Microarray analysis revealed downregulation of several proinflammatory genes in the stabilin-1high monocytes when compared with stabilin-1low monocytes. When cocultured with stabilin-1high monocytes, IFN-g synthesis by T cells was diminished in Ag-recall assays. Knockdown of stabilin-1 in monocytes increased the synthesis of several proinflammatory molecules, including TNF-a, and supported high IFN-g and low IL-4 and IL-5 production by T cells in Ag-specific stimulation assays. Anti–stabilin-1 Ab treatment also led to increased IFN-g synthesis in the recall assays. In clinical settings, the expression of stabilin-1 was diminished on blood monocytes and tissue macrophages under proinflammatory conditions. These data define stabilin-1 as a new immunosuppressive molecule and suggest that stabilin-1high monocytes may dampen proinflammatory reactions in vivo. The Journal of Immunology, 2016, 196: 000–000. Downloaded from onocytes are bone marrow–derived subsets of circu- subset of tumor-associated macrophages (11). Stabilin-1 is also lating WBCs, which can differentiate into mac- expressed in monocytes during specific disease conditions, like M rophages and dendritic cells after migration into hypercholesterolemia, but reported to be absent from normal different tissues (1). Monocytes play an important role in tissue monocytes (12). In macrophages, stabilin-1 acts as a scavenging homeostasis, wound healing, and host defense reactions against receptor during endocytosis of selected proteins such as oxidized microbes, other inflammatory stimuli, and tumor cells. Based on and acetylated low-density lipoprotein (Ac-LDL), OVA, SPARC, http://www.jimmunol.org/ the expression of CD14 and CD16, human monocytes are classi- and placental lactogen (13–16). It has also been reported to be fied into three subsets, which also have different transcriptomes involved in bacterial binding (17), clearance of apoptotic cell (1–3). The majority (80–90%) of blood monocytes belong to the bodies (18), and wound healing (10) and in adhesion and trans- CD14+CD162 subset, which, together with the CD14+CD16+ migration of placental leukocytes through endothelial cells (19). subpopulation, are proinflammatory monocytes analogous to Although stabilin-1 is a useful marker for a subset of type 2 hi hi low mouse Ly6C CCR2 CX3CR1 cells. The nonclassical minor macrophages, nothing is known about its functional role during CD14dimCD16+ human monocyte population, in contrast, resem- the polarization of immune responses. low low hi bles mouse Ly6C CCR2 CX3CR1 cells, which constantly In this study, we unexpectedly found definitive expression of patrol the vessels and are involved in cell maintenance and healing stabilin-1 on the surface of normal blood monocytes when using by guest on October 1, 2021 functions (3, 4). new sensitive Abs. In functional experiments, the stabilin-1low Stabilin-1 (also known as CLEVER-1 or FEEL-1) is a multi- monocyte population and stabilin-1 knockdown monocytes sup- functional type I transmembrane protein most prominently ex- ported the generation of robust proinflammatory immune re- pressed on selected endothelial cells and alternatively activated sponses. Notably, ligation of monocyte stabilin-1 by an anti– M2 macrophages (5–9). Stabilin-1 synthesis is induced in mac- stabilin-1 Ab also diverted Ag-specific responses into the Th1 rophages during inflammation (10), and it is highly expressed in a direction. These data thus define stabilin-1 as a novel immune modulator. *MediCity Research Laboratory, University of Turku, Turku 20520, Finland; †Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku Materials and Methods ‡ 20520, Finland; Turku Doctoral Programme of Biomedical Sciences, University Study populations of Turku, Turku 20520, Finland; xDepartment of Medical Biochemistry and Genetics, University of Turku, Turku 20520, Finland; {Department of Obstetrics and Gynecol- ‖ Blood samples from healthy volunteers, tetanus-vaccinated persons (pre- ogy, University of Turku, Turku 20520, Finland; and Department of Medical Mi- viously vaccinated individuals who had received a booster injection within crobiology and Immunology, University of Turku, Turku 20520, Finland past 2 y), and timothy grass–allergic (self-reported) persons were collected ORCID: 0000-0001-7435-5398 (S.P.). using venipuncture. All donors gave their informed consent. Received for publication February 4, 2015. Accepted for publication October 28, Blood samples and samples of placenta and placental bed were taken at 2015. elective caesarean sections performed for defined obstetrical indications from women with normal pregnancies and from those with pre-eclampsia at The sequences presented in this article have been submitted to the Gene Expression Omnibus under accession numbers GSE63519 and GSE63807. the Department of Obstetrics in Turku University Central Hospital. These samples were collected with permission of the Ethical Committee of the Address correspondence and reprint requests to Prof. Marko Salmi, MediCity Re- University of Turku, and a written consent was signed by all patients search Laboratory, University of Turku, Tykisto¨katu 6A, Turku FIN-20520, Finland. participating in this study. Apart from the treating clinician (E.E.), the E-mail address: marko.salmi@utu.fi patients remained anonymous to the other investigators. The online version of this article contains supplemental material. Abbreviations used in this article: Ac-LDL, acetylated low-density lipoprotein; DE, Abs differentially expressed; FMSC, Finnish Microarray and Sequencing Centre; GO, 9-11 (a rat IgG2a) and 3-372 (a mouse IgG1) are against human stabilin-1 Gene Ontology; GSEA, Gene Set Enrichment Analysis; IPA, Ingenuity Pathway Analysis; OSM, oncostatin M; qPCR, quantitative PCR; RNAseq, RNA sequencing; (8, 19). The other mAbs used were: CD14- FITC (mouse IgG2a; Southern RQ, relative quantification; SAA, serum amyloid A; SFC, spot-forming cell; siRNA, Biotechnology Associates), CD16-PerCP–Cy5.5 (mouse IgG1; BD Phar- small interfering RNA. mingen), HLA-DR–allophycocyanin (mouse IgG2a; BD Pharmingen), and macrophage mannose receptor (CD206, clone 15-2 MRC-1; Lifespan Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$30.00 Biosciences). As isotype controls, IgG2a-FITC, IgG1-PerCP–Cy5.5, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500257 2 IMMUNOSUPPRESSIVE STABILIN-1 IN MONOCYTES IgG2a-allophycocyanin (all from BD Pharmingen), MEL-14 (rat IgG2a), anti-biotin secondary Ab (1:1000), and spots were developed with BCI- and 3G6 (mouse IgG1) were used. The second-stage reagents were PE- NBT solution. conjugated goat anti-mouse IgG (a whole Ig molecule from Southern The specific spot numbers for each coculture condition were counted Biotechnology Associates) and PE-conjugated goat polyclonal F(ab)2 microscopically by subtracting the number of spots recorded in three against anti-rat F(ab)2 (Abcam). F(ab)2 fragments of 9-11 and MEL-14 controls: 1) the cocultures of the corresponding monocytes and T cells were generated commercially by GenScript. without the Ag; 2) the control cultures of the corresponding monocytes with the Ag only (no T cells); and 3) the control cultures of the T cells and Immunofluorescence stainings and FACS analyses the Ag only (no monocytes) from the number of spots recorded in the cocultures in the presence of the monocytes, T cells, and Ag. To normalize Blood samples were collected in EDTA tubes. RBCs were lysed using a the interindividual variation in the absolute numbers of spots, the specific commercial lysis buffer (BD Pharm Lyse; BD Biosciences). After pre- blocking with human Ig (100 mg/ml; KIOVIG from Baxter) the leukocytes were sequentially incubated with anti–stabilin-1 9-11 F(ab)2 or nega- tive control MEL-14 F(ab)2 (20 mg/ml) and PE-conjugated goat anti-rat F(ab)2–F(ab)2 Ab. In monocyte phenotyping experiments, the cells
Load more

Recommended publications
  • Multivariate Meta-Analysis of Differential Principal Components Underlying Human Primed and Naive-Like Pluripotent States
    bioRxiv preprint doi: https://doi.org/10.1101/2020.10.20.347666; this version posted October 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. October 20, 2020 To: bioRxiv Multivariate Meta-Analysis of Differential Principal Components underlying Human Primed and Naive-like Pluripotent States Kory R. Johnson1*, Barbara S. Mallon2, Yang C. Fann1, and Kevin G. Chen2*, 1Intramural IT and Bioinformatics Program, 2NIH Stem Cell Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA Keywords: human pluripotent stem cells; naive pluripotency, meta-analysis, principal component analysis, t-SNE, consensus clustering *Correspondence to: Dr. Kory R. Johnson ([email protected]) Dr. Kevin G. Chen ([email protected]) 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.10.20.347666; this version posted October 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. ABSTRACT The ground or naive pluripotent state of human pluripotent stem cells (hPSCs), which was initially established in mouse embryonic stem cells (mESCs), is an emerging and tentative concept. To verify this important concept in hPSCs, we performed a multivariate meta-analysis of major hPSC datasets via the combined analytic powers of percentile normalization, principal component analysis (PCA), t-distributed stochastic neighbor embedding (t-SNE), and SC3 consensus clustering.
    [Show full text]
  • PADI4 Mouse Monoclonal Antibody [Clone ID: OTI5C10] Product Data
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for CF504896 PADI4 Mouse Monoclonal Antibody [Clone ID: OTI5C10] Product data: Product Type: Primary Antibodies Clone Name: OTI5C10 Applications: IHC, WB Recommended Dilution: WB 1:2000, IHC 1:150 Reactivity: Human Host: Mouse Isotype: IgG1 Clonality: Monoclonal Immunogen: Human recombinant protein fragment correspongding to amino acids 299-588 of human PADI4(NP_036519) produced in E.coli. Formulation: Lyophilized powder (original buffer 1X PBS, pH 7.3, 8% trehalose) Reconstitution Method: For reconstitution, we recommend adding 100uL distilled water to a final antibody concentration of about 1 mg/mL. To use this carrier-free antibody for conjugation experiment, we strongly recommend performing another round of desalting process. (OriGene recommends Zeba Spin Desalting Columns, 7KMWCO from Thermo Scientific) Purification: Purified from mouse ascites fluids or tissue culture supernatant by affinity chromatography (protein A/G) Conjugation: Unconjugated Storage: Store at -20°C as received. Stability: Stable for 12 months from date of receipt. Predicted Protein Size: 73.9 kDa Gene Name: Homo sapiens peptidyl arginine deiminase 4 (PADI4), mRNA. Database Link: NP_036519 Entrez Gene 23569 Human Q9UM07 This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 4 PADI4 Mouse Monoclonal Antibody [Clone ID: OTI5C10] – CF504896 Background: This gene is a member of a gene family which encodes enzymes responsible for the conversion of arginine residues to citrulline residues.
    [Show full text]
  • Deimination, Intermediate Filaments and Associated Proteins
    International Journal of Molecular Sciences Review Deimination, Intermediate Filaments and Associated Proteins Julie Briot, Michel Simon and Marie-Claire Méchin * UDEAR, Institut National de la Santé Et de la Recherche Médicale, Université Toulouse III Paul Sabatier, Université Fédérale de Toulouse Midi-Pyrénées, U1056, 31059 Toulouse, France; [email protected] (J.B.); [email protected] (M.S.) * Correspondence: [email protected]; Tel.: +33-5-6115-8425 Received: 27 October 2020; Accepted: 16 November 2020; Published: 19 November 2020 Abstract: Deimination (or citrullination) is a post-translational modification catalyzed by a calcium-dependent enzyme family of five peptidylarginine deiminases (PADs). Deimination is involved in physiological processes (cell differentiation, embryogenesis, innate and adaptive immunity, etc.) and in autoimmune diseases (rheumatoid arthritis, multiple sclerosis and lupus), cancers and neurodegenerative diseases. Intermediate filaments (IF) and associated proteins (IFAP) are major substrates of PADs. Here, we focus on the effects of deimination on the polymerization and solubility properties of IF proteins and on the proteolysis and cross-linking of IFAP, to finally expose some features of interest and some limitations of citrullinomes. Keywords: citrullination; post-translational modification; cytoskeleton; keratin; filaggrin; peptidylarginine deiminase 1. Introduction Intermediate filaments (IF) constitute a unique macromolecular structure with a diameter (10 nm) intermediate between those of actin microfilaments (6 nm) and microtubules (25 nm). In humans, IF are found in all cell types and organize themselves into a complex network. They play an important role in the morphology of a cell (including the nucleus), are essential to its plasticity, its mobility, its adhesion and thus to its function.
    [Show full text]
  • A Novel PAD4/SOX4/PU.1 Signaling Pathway Is Involved in the Committed Differentiation of Acute Promyelocytic Leukemia Cells Into Granulocytic Cells
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 3 A novel PAD4/SOX4/PU.1 signaling pathway is involved in the committed differentiation of acute promyelocytic leukemia cells into granulocytic cells Guanhua Song1, Lulu Shi1, Yuqi Guo1, Linchang Yu1, Lin Wang2, Xiaoyu Zhang1, Lianlian Li1, Yang Han1, Xia Ren1, Qiang Guo1, Kehong Bi3, Guosheng Jiang1 1 Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong, China 2Research Center for Medicinal Biotechnology, Shandong Academy of Medicinal Sciences, Jinan, Shandong, China 3Qianfoshan Hospital of Shandong, Jinan, Shandong, China Correspondence to: Kehong Bi, e-mail: [email protected] Guosheng Jiang, e-mail: [email protected] Keywords: PADI4, methylation, differentiation, leukemia Received: April 24, 2015 Accepted: November 20, 2015 Published: December 10, 2015 ABSTRACT All-trans retinoic acid (ATRA) treatment yields cure rates > 80% through proteasomal degradation of the PML-RARα fusion protein that typically promotes acute promyelocytic leukemia (APL). However, recent evidence indicates that ATRA can also promote differentiation of leukemia cells that are PML-RARα negative, such as HL-60 cells. Here, gene expression profiling of HL-60 cells was used to investigate the alternative mechanism of impaired differentiation in APL. The expression of peptidylarginine deiminase 4 (PADI4), encoding PAD4, a protein that post-translationally converts arginine into citrulline, was restored during ATRA- induced differentiation. We further identified that hypermethylation in the PADI4 promoter was associated with its transcriptional repression in HL-60 and NB4 (PML- RARα positive) cells. Functionally, PAD4 translocated into the nucleus upon ATRA exposure and promoted ATRA-mediated differentiation.
    [Show full text]
  • Supplementary Materials
    Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine
    [Show full text]
  • Regulation of Protein Citrullination Through P53/PADI4 Network in DNA Damage Response
    Published OnlineFirst October 20, 2009; DOI: 10.1158/0008-5472.CAN-09-2280 Molecular Biology, Pathobiology, and Genetics Regulation of Protein Citrullination through p53/PADI4Network in DNA Damage Response Chizu Tanikawa,1 Koji Ueda,3 Hidewaki Nakagawa,3 Nobuaki Yoshida,2 Yusuke Nakamura,1 and Koichi Matsuda1 1Laboratory of Molecular Medicine, Human Genome Center, 2Division of Gene Expression and Regulation, Institute of Medical Science, the University of Tokyo; and 3Laboratory for Biomarker Development, Center for Genomic Medicine, RIKEN, Tokyo, Japan Abstract modulation of PTMs. However, the role of p53 in the regulation of Upon a wide range of cellular stresses, p53 is activated and PTMs has not yet been elucidated. inhibits malignant transformation through the transcription- Citrullination (also referred to as deimination) is one form of PTMs which converts an arginine residue in protein into a citrulline al regulation of its target genes related to apoptosis, cell 2+ cycle arrest, and DNA repair. However, its involvement in residue (5). This reaction is mediated by a Ca -dependent enzyme posttranslational modifications of proteins has not yet been called peptidylarginine deiminase. Citrullination of proteins results well characterized. Here, we report the novel role of p53 in in a loss of positive charge and causes a significant biochemical the regulation of protein citrullination. p53 transactivated change. For example, PADI4 was shown to convert monomethyl- peptidylarginine deiminase type 4 (PADI4) through an intro- arginine residues of histone H3 and H4 to citrullines and negatively nic p53-binding site. The PADI4 gene encodes an enzyme regulate gene expression (6, 7). catalyzing the citrullination of arginine residues in proteins, On the other hand, citrullinated peptides/proteins are recog- – and ectopic expression of p53 or PADI4 induced protein nized as non self-proteins and subsequently activate immune citrullination.
    [Show full text]
  • Endogenous PAD4 in Breast Cancer Cells Mediates Cancer Extracellular
    Published OnlineFirst March 19, 2020; DOI: 10.1158/1541-7786.MCR-19-0018 MOLECULAR CANCER RESEARCH | NEW HORIZONS IN CANCER BIOLOGY Endogenous PAD4 in Breast Cancer Cells Mediates Cancer Extracellular Chromatin Network Formation and Promotes Lung Metastasis Lai Shi1,2, Huanling Yao3, Zheng Liu3, Ming Xu2,4, Allan Tsung5, and Yanming Wang1,2,3,6 ABSTRACT ◥ Peptidyl arginine deiminase 4 (PAD4/PADI4) is a posttransla- Implications: This study shows that PADI4 can mediate the tional modification enzyme that converts protein arginine or mono- formation of CECNs in 4T1 cells, and that endogenous PADI4 methylarginine to citrulline. The PAD4-mediated hypercitrullina- plays an essential role in breast cancer lung metastasis. tion reaction in neutrophils causes the release of nuclear chromatin to form a chromatin network termed neutrophil extracellular traps Visual Overview: http://mcr.aacrjournals.org/content/molcanres/ (NET). NETs were first described as antimicrobial fibers that bind 00/00/0000/F1.large.jpg. and kill bacteria. However, it is not known whether PAD4 can mediate the release of chromatin DNA into the extracellular space of cancer cells. Here, we report that murine breast cancer 4T1 cells expressing high levels of PADI4 can release cancer extracellular chromatin networks (CECN) in vitro and in vivo. Deletion of Padi4 using CRISPR/Cas9 abolished CECN formation in 4T1 cells. Padi4 deletion from 4T1 cells also reduced the rate of tumor growth in an allograft model, and decreased lung metastasis by 4T1 breast cancers. DNase I treatment, which degrades extracellular DNA including CECNs, also reduced breast to lung metastasis of Padi4 wild-type 4T1 cells in allograft experiments in the Padi4-knockout mice.
    [Show full text]
  • PADI4) Rs1748033 Polymorphism and Susceptibility to Rheumatoid Arthritis in Gorgan, Northeast of Iran
    Original Research Article Association Assessment of Peptidylarginine Deiminase Type 4 (PADI4) rs1748033 polymorphism and susceptibility to rheumatoid arthritis in Gorgan, Northeast of Iran Aytekin Aghchelli1, Yaghoub Yazdani2*, Hadi Bazzazi3, Mehrdad Aghaei4 1Department of Biology, Gorgan Branch, Islamic Azad University, Gorgan, Iran 2 Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran 3 Department of Medical Laboratory Sciences, Gorgan Branch, Islamic Azad University, Gorgan, Iran 4Golestan Rheumatology Research Center (GRRC), Golestan University of Medical Sciences, Gorgan, Iran ABSTRACT Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease in which both genetic and environmental factors could be involved. Peptidyl arginine deiminase type IV (PADI4) is an enzyme responsible for the posttranslational conversion of arginine residues into citrulline. The association between PADI4 single nucleotide polymorphisms (SNPs) and RA susceptibility have been reported. Here, we aimed to assess the association of PADI4-104 (rs1748033) variant with the susceptibility to RA in an Iranian population in northeast of Iran. Materials and methods: A total of 130 RA patients and 128 age- and sex-matched healthy donors were recruited. The amplification-refractory mutation system with allele specific primers was used to detect PADI4-104 SNP. Disease activity was calculated using Disease Activity Scale 28a. SPSS 22.0 and SNPstat online software were used to analyze data using relevant statistical tests. Results: The CC genotype was more frequent in healthy subjects compared to RA patients. Setting the CC genotype as the reference, the TT genotype was significantly associated with increased risk of RA [OR = 2.11, 95% CI (1.45–3.07), P-value = 0.0001].
    [Show full text]
  • Regulation of Histone Modification and Chromatin Structure by the P53–PADI4 Pathway
    ARTICLE Received 5 Dec 2011 | Accepted 11 Jan 2012 | Published 14 Feb 2012 DOI: 10.1038/ncomms1676 Regulation of histone modification and chromatin structure by the p53–PADI4 pathway Chizu Tanikawa1, Martha Espinosa1,2, Akari Suzuki3, Ken Masuda1, Kazuhiko Yamamoto3,4, Eiju Tsuchiya5,6, Koji Ueda7, Yataro Daigo1,8, Yusuke Nakamura1 & Koichi Matsuda1 Histone proteins are modified in response to various external signals; however, their mechanisms are still not fully understood. Citrullination is a post-transcriptional modification that converts arginine in proteins into citrulline. Here we show in vivo and in vitro citrullination of the arginine 3 residue of histone H4 (cit-H4R3) in response to DNA damage through the p53–PADI4 pathway. We also show DNA damage-induced citrullination of Lamin C. Cit-H4R3 and citrullinated Lamin C localize around fragmented nuclei in apoptotic cells. Ectopic expression of PADI4 leads to chromatin decondensation and promotes DNA cleavage, whereas Padi4 − / − mice exhibit resistance to radiation-induced apoptosis in the thymus. Furthermore, the level of cit-H4R3 is negatively correlated with p53 protein expression and with tumour size in non-small cell lung cancer tissues. Our findings reveal that cit-H4R3 may be an ‘apoptotic histone code’ to detect damaged cells and induce nuclear fragmentation, which has a crucial role in carcinogenesis. 1 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan. 2 Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies, Mexico City 07360, Mexico. 3 Laboratory for Rheumatic Diseases, Center for Genomic Medicine, RIKEN, Yokohama 2300045, Japan.
    [Show full text]
  • The Biological Age of a Bloodstain Donor Author(S): Jack Ballantyne, Ph.D
    The author(s) shown below used Federal funding provided by the U.S. Department of Justice to prepare the following resource: Document Title: The Biological Age of a Bloodstain Donor Author(s): Jack Ballantyne, Ph.D. Document Number: 251894 Date Received: July 2018 Award Number: 2009-DN-BX-K179 This resource has not been published by the U.S. Department of Justice. This resource is being made publically available through the Office of Justice Programs’ National Criminal Justice Reference Service. Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S. Department of Justice. National Center for Forensic Science University of Central Florida P.O. Box 162367 · Orlando, FL 32826 Phone: 407.823.4041 Fax: 407.823.4042 Web site: http://www.ncfs.org/ Biological Evidence _________________________________________________________________________________________________________ The Biological Age of a Bloodstain Donor FINAL REPORT May 27, 2014 Department of Justice, National Institute of justice Award Number: 2009-DN-BX-K179 (1 October 2009 – 31 May 2014) _________________________________________________________________________________________________________ Principal Investigator: Jack Ballantyne, PhD Professor Department of Chemistry Associate Director for Research National Center for Forensic Science P.O. Box 162367 Orlando, FL 32816-2366 Phone: (407) 823 4440 Fax: (407) 823 4042 e-mail: [email protected] 1 This resource was prepared by the author(s) using Federal funds provided by the U.S. Department of Justice. Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S.
    [Show full text]
  • Increased Peptidylarginine Deiminases Expression During The
    Lai et al. Arthritis Research & Therapy (2019) 21:108 https://doi.org/10.1186/s13075-019-1896-9 RESEARCHARTICLE Open Access Increased peptidylarginine deiminases expression during the macrophage differentiation and participated inflammatory responses Ning-Sheng Lai1,2†, Hui-Chun Yu1†, Chien-Hsueh Tung1,2, Kuang-Yung Huang1,2, Hsien-Bin Huang3 and Ming-Chi Lu1,2* Abstract Objective: To investigate the expression of peptidylarginine deiminases (PADIs) during macrophage differentiation and its role in inflammatory responses. Methods: The protein expression of PADI2, PADI4, and citrullinated histone 3 in U937 cells, differentiated macrophages, and macrophages stimulated with lipopolysaccharides (LPS) were analyzed by Western blotting. Three PADI inhibitors were used for assessing their effects on the secretion of proinflammatory cytokines in macrophages. The differential expressed citrullinated proteins during macrophage differentiation were probed by self-prepared anti-citrullinated protein antibodies, and the reactive bands were sent for proteomic analyses. Transfection studies were conducted to search for the functions of specific proteins. A specific protein was cloned and citrullinated for its protein binding study. Results: The expression of PADI2 and PADI4 markedly increased during macrophage differentiation, whereas the formation of citrullinated histone 3 increased after stimulated with lipopolysaccharides. Three PADI inhibitors suppressed the LPS mediated proinflammatory cytokines secretion, but did not affect the expression of PADI2 and PADI4. Plasminogen activator inhibitor-2 (PAI-2) was citrullinated during macrophage differentiation. The expression of PAI-2 increased during macrophage differentiation and further increased after stimulated with LPS. Suppressed PAI-2 expression decreased the expression and secretion of proinflammatory cytokines. Decreased PADI2 expression also suppressed the expression of PAI-2 and protein levels of citrullinated PAI-2.
    [Show full text]
  • Generative Modeling of Multi-Mapping Reads with Mhi-C
    Manuscript submitted to eLife 1 Generative Modeling of 2 Multi-mapping Reads with mHi-C 3 Advances Analysis of Hi-C Studies 1 2,3 1,4* 4 Ye Zheng , Ferhat Ay , Sündüz Keleş *For correspondence: [email protected] (SK) 1 2 5 Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706, USA; La 3 6 Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA; School of Medicine, 4 7 University of California San Diego, La Jolla, CA 92093, USA; Department of Biostatistics 8 and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53706, USA 9 10 Abstract Current Hi-C analysis approaches are unable to account for reads that align to multiple 11 locations, and hence underestimate biological signal from repetitive regions of genomes. We 12 developed and validated mHi-C,amulti-read mapping strategy to probabilistically allocate Hi-C 13 multi-reads. mHi-C exhibited superior performance over utilizing only uni-reads and heuristic 14 approaches aimed at rescuing multi-reads on benchmarks. Specifically, mHi-C increased the 15 sequencing depth by an average of 20% resulting in higher reproducibility of contact matrices and 16 detected interactions across biological replicates. The impact of the multi-reads on the detection of 17 significant interactions is influenced marginally by the relative contribution of multi-reads to the 18 sequencing depth compared to uni-reads, cis-to-trans ratio of contacts, and the broad data quality 19 as reflected by the proportion of mappable reads of datasets. Computational experiments 20 highlighted that in Hi-C studies with short read lengths, mHi-C rescued multi-reads can emulate the 21 effect of longer reads.
    [Show full text]