DOCSLIB.ORG

The Role of TIMP3 in Models of Inflammation and Immunity

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of TIMP3 in Models of Inflammation and Immunity The Role of TIMP3 in Models of Inflammation and Immunity By David Smookler March 2010 A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate department of Laboratory Medicine and Pathobiology University of Toronto © copyright by David Smookler 2010 ABSTRACT The Role of TIMP3 in Models of Inflammation and Immunity by David Smookler a PhD thesis for the Department of Laboratory Medicine and Pathobiology University of Toronto, 2010 The inter-relation between inflammation, the immune system and leukocytes is multifaceted, with communication between stroma and immune cells mediated by cytokines, growth factors, chemokines, integrins and other molecules. Proteolysis plays an important role in regulating these molecules. Proteolytic cleavage can not only destroy some molecules but can activate or shed others, converting local juxtacrine signalling proteins into effectors that act at a distance. Shedding can also convert membrane-bound receptors into soluble ligand-binding inhibitors. Finally, cleavage can convert agonist molecules into antagonists. As a wide-ranging inhibitor of metalloproteinases, tissue inhibitor of metalloproteinase 3 (TIMP3) has the potential to down-regulate many of these activities. We explore the role of TIMP3 in the regulation of inflammation, revealing that loss of TIMP3 leads to a more rapid increase of soluble TNF, higher levels of soluble TNF receptors and ultimately to increased TNF signalling in systemic inflammation. We also demonstrate TIMP3 loss impacts local inflammation. In addition we investigate the importance of TIMP3 in the expansion of hematopoietic cells. ii ACKNOWLEDGMENTS I would like to thank Dr. Rama Khokha for her unwavering support over the years. Actually there has been a bit of wavering, but overall she has been a lighthouse to me and my thanks are deep and sincere. I would also like to thank Marco DiGrappa who by virtue of his intelligence and unstinting helpfulness coupled with a humorous state of pessimism and self-deprecation has taught me never to take myself too seriously, and to feel I will always have a sympathetic ear when something goes wrong. I would like to thank Hart Jackson, Alison Aiken and Sam Molyneux for the respect they pay me, probably as an older statesman of the lab but I hope respect earned by what I share with them. I’d like to thank Alex Beristain for reminding me that “older statesman” essentially means “old man”. I’d like to thank Adi Murthy for reminding me of the scientific enthusiasm that can be brought to my field, and I’d like to thank Virginie Defamie for the unconditional warmth with which I am greeted whenever I appear at the lab. I’d like to thank Purna Joshi for being an example of dogged focus and perseverance, not afraid to take on Herculean projects while other demands are made upon her. I would like to thank Iris Fang for her patience and generous helpfulness. I’d like to thank Trevor McKee for watching out for the post-docs’ welfare as I soon hope to join their ranks. I thank Gordon Duncan, whose practical advice was instrumental to my work, and Bill Sukloff who’s instrument, this laptop, made writing up my work practical. I would also like to thank former members of the Khokha lab Zam Kassiri and Geoff Wood for their guidance and support. I thank Swami Narala for reminding me that gratitude is payment in a currency that costs little but is worth much. And Linda, who put up with it all, I thank you. iii TABLE OF CONTENTS Chapter 1: INTRODUCTION The Extracellular Matrix--------------------------------------------------------------------------1 Collagens -------------------------------------------------------------------------------------2 Glycosaminoglycans and Proteoglycans -------------------------------------------------3 ECM glycoproteins -------------------------------------------------------------------------4 Proteases in the Mammalian Genome ----------------------------------------------------------6 Matrix Metalloproteinases -----------------------------------------------------------------6 MMP structure-------------------------------------------------------------6 Types of MMPs------------------------------------------------------------7 Roles of MMPs in normal physiology --------------------------------10 MMPs target growth factor signalling in several ways -------------12 Regulation of MMPs ----------------------------------------------------13 ADAMTSs----------------------------------------------------------------------------------14 ADAMs -------------------------------------------------------------------------------------14 TACE----------------------------------------------------------------------16 Metalloproteinases in inflammation-----------------------------------------------------19 Tissue Inhibitors of Metalloproteinases ------------------------------------------------------20 TIMP Structure-----------------------------------------------------------------------------21 TIMP3 ---------------------------------------------------------------------------------------21 Structural interaction of TIMP3 with TACE -------------------------22 iv Inflammation---------------------------------------------------------------------------------------26 Systemic Inflammatory Response Syndrome (SIRS) --------------------------------29 Lipopolysaccharide (LPS)----------------------------------------------------------------30 Tumour Necrosis Factor (TNF)----------------------------------------------------------31 Expression of TNF and TNF Receptors ------------------------------34 TNF Signal Transduction -----------------------------------------------34 TNF and IL-6-------------------------------------------------------------39 Nitric Oxide---------------------------------------------------------------------------------42 TIMP3 and Hematopoiesis ----------------------------------------------------------------------42 MPs targeted by TIMP3 affect hematopoietic growth factor signalling------------43 MPs are involved in the trafficking of hematopoietic cells --------------------------46 TIMPs influence hematopoiesis via MPi and non-MPi mechanisms---------------46 Rationale for the Thesis--------------------------------------------------------------------------47 Chapter 2: MATERIALS AND METHODS Mice --------------------------------------------------------------------------------------------------49 Reagents---------------------------------------------------------------------------------------------50 ELISAs ----------------------------------------------------------------------------------------------50 Statistical Analysis --------------------------------------------------------------------------------51 Tissue preparation for Western blots and TACE assay -----------------------------------51 Protein Quantification----------------------------------------------------------------------------52 TACE assay-----------------------------------------------------------------------------------------52 v Western blot antibodies --------------------------------------------------------------------------53 Quantitative PCR ---------------------------------------------------------------------------------54 Alanine aminotransferase (ALT) analysis----------------------------------------------------55 Synthetic metalloproteinase inhibitors--------------------------------------------------------56 Heart effluent---------------------------------------------------------------------------------------56 Nitric oxide analysis-------------------------------------------------------------------------------56 Peripheral blood analysis ------------------------------------------------------------------------57 Skin challenge --------------------------------------------------------------------------------------57 Memory cytotoxic lymphocyte analysis ------------------------------------------------------57 Hematopoiesis --------------------------------------------------------------------------------------58 Reproducibility and variation of results ------------------------------------------------------61 Chapter 3: TIMP3 Regulates TNF-Dependent Systemic Inflammation ABSTRACT ----------------------------------------------------------------------------------------63 INTRODUCTION---------------------------------------------------------------------------------64 RESULTS -------------------------------------------------------------------------------------------66 -/- Inactivated bacteria induces greater TNF release in Timp3 mice ----------------------66 -/- Timp3 mice are highly sensitive to LPS-induced septic shock ------------------------71 -/- p55 pathway is required for heightened inflammation in Timp3 mice ----------------73 -/- -/- Timp4 mice do not share the sensitivity to LPS found in Timp3 mice --------------75 DISCUSSION --------------------------------------------------------------------------------------77 vi Chapter 4: Investigation of the Organ Response to Inflammatory Challenge in Timp3-/- Mice ABSTRACT ----------------------------------------------------------------------------------------81 INTRODUCTION --------------------------------------------------------------------------------82 RESULTS -------------------------------------------------------------------------------------------84 -/- Timp3 livers show normal production of and sensitivity to IL-6 ----------------------84 -/- In response to LPS, JNK activation is greater in Timp3 livers -------------------------86 Comparison of TNF levels in Timp3-/- versus wild-type
Load more

Recommended publications
  • Chromosomal Aberrations in Head and Neck Squamous Cell Carcinomas in Norwegian and Sudanese Populations by Array Comparative Genomic Hybridization
    825-843 12/9/08 15:31 Page 825 ONCOLOGY REPORTS 20: 825-843, 2008 825 Chromosomal aberrations in head and neck squamous cell carcinomas in Norwegian and Sudanese populations by array comparative genomic hybridization ERIC ROMAN1,2, LEONARDO A. MEZA-ZEPEDA3, STINE H. KRESSE3, OLA MYKLEBOST3,4, ENDRE N. VASSTRAND2 and SALAH O. IBRAHIM1,2 1Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Jonas Lies vei 91; 2Department of Oral Sciences - Periodontology, Faculty of Medicine and Dentistry, University of Bergen, Årstadveien 17, 5009 Bergen; 3Department of Tumor Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, 0310 Oslo; 4Department of Molecular Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway Received January 30, 2008; Accepted April 29, 2008 DOI: 10.3892/or_00000080 Abstract. We used microarray-based comparative genomic logical parameters showed little correlation, suggesting an hybridization to explore genome-wide profiles of chromosomal occurrence of gains/losses regardless of ethnic differences and aberrations in 26 samples of head and neck cancers compared clinicopathological status between the patients from the two to their pair-wise normal controls. The samples were obtained countries. Our findings indicate the existence of common from Sudanese (n=11) and Norwegian (n=15) patients. The gene-specific amplifications/deletions in these tumors, findings were correlated with clinicopathological variables. regardless of the source of the samples or attributed We identified the amplification of 41 common chromosomal carcinogenic risk factors. regions (harboring 149 candidate genes) and the deletion of 22 (28 candidate genes). Predominant chromosomal alterations Introduction that were observed included high-level amplification at 1q21 (harboring the S100A gene family) and 11q22 (including Head and neck squamous cell carcinoma (HNSCC), including several MMP family members).
    [Show full text]
  • The Diverse Roles of TIMP-3: Insights Into Degenerative Diseases of the Senescent Retina and Brain
    cells Review The Diverse Roles of TIMP-3: Insights into Degenerative Diseases of the Senescent Retina and Brain Jennifer M. Dewing 1, Roxana O. Carare 1, Andrew J. Lotery 1,2 and J. Arjuna Ratnayaka 1,* 1 Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP806, Tremona Road, Southampton SO16 6YD, UK; [email protected] (J.M.D.); [email protected] (R.O.C.); [email protected] (A.J.L.) 2 Eye Unit, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK * Correspondence: [email protected]; Tel.: +44-238120-8183 Received: 13 November 2019; Accepted: 19 December 2019; Published: 21 December 2019 Abstract: Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a component of the extracellular environment, where it mediates diverse processes including matrix regulation/turnover, inflammation and angiogenesis. Rare TIMP-3 risk alleles and mutations are directly linked with retinopathies such as age-related macular degeneration (AMD) and Sorsby fundus dystrophy, and potentially, through indirect mechanisms, with Alzheimer’s disease. Insights into TIMP-3 activities may be gleaned from studying Sorsby-linked mutations. However, recent findings do not fully support the prevailing hypothesis that a gain of function through the dimerisation of mutated TIMP-3 is responsible for retinopathy. Findings from Alzheimer’s patients suggest a hitherto poorly studied relationship between TIMP-3 and the Alzheimer’s-linked amyloid-beta (Aβ) proteins that warrant further scrutiny. This may also have implications for understanding AMD as aged/diseased retinae contain high levels of Aβ. Findings from TIMP-3 knockout and mutant knock-in mice have not led to new treatments, particularly as the latter does not satisfactorily recapitulate the Sorsby phenotype.
    [Show full text]
  • Suramin Inhibits Osteoarthritic Cartilage Degradation by Increasing Extracellular Levels
    Molecular Pharmacology Fast Forward. Published on August 10, 2017 as DOI: 10.1124/mol.117.109397 This article has not been copyedited and formatted. The final version may differ from this version. MOL #109397 Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3). Anastasios Chanalaris, Christine Doherty, Brian D. Marsden, Gabriel Bambridge, Stephen P. Wren, Hideaki Nagase, Linda Troeberg Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Downloaded from Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK (A.C., C.D., G.B., H.N., L.T.); Alzheimer’s Research UK Oxford Drug Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK (S.P.W.); Structural Genomics Consortium, molpharm.aspetjournals.org University of Oxford, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Headington, Oxford, OX3 7DQ (BDM). at ASPET Journals on September 29, 2021 1 Molecular Pharmacology Fast Forward. Published on August 10, 2017 as DOI: 10.1124/mol.117.109397 This article has not been copyedited and formatted. The final version may differ from this version. MOL #109397 Running title: Repurposing suramin to inhibit osteoarthritic cartilage loss. Corresponding author: Linda Troeberg Address: Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK Phone number: +44 (0)1865 612600 E-mail: [email protected] Downloaded
    [Show full text]
  • Telomere-To-Telomere Assembly of a Complete Human X Chromosome W
    https://doi.org/10.1038/s41586-020-2547-7 Accelerated Article Preview Telomere-to-telomere assembly of a W complete human X chromosome E VI Received: 30 July 2019 Karen H. Miga, Sergey Koren, Arang Rhie, Mitchell R. Vollger, Ariel Gershman, Andrey Bzikadze, Shelise Brooks, Edmund Howe, David Porubsky, GlennisE A. Logsdon, Accepted: 29 May 2020 Valerie A. Schneider, Tamara Potapova, Jonathan Wood, William Chow, Joel Armstrong, Accelerated Article Preview Published Jeanne Fredrickson, Evgenia Pak, Kristof Tigyi, Milinn Kremitzki,R Christopher Markovic, online 14 July 2020 Valerie Maduro, Amalia Dutra, Gerard G. Bouffard, Alexander M. Chang, Nancy F. Hansen, Amy B. Wilfert, Françoise Thibaud-Nissen, Anthony D. Schmitt,P Jon-Matthew Belton, Cite this article as: Miga, K. H. et al. Siddarth Selvaraj, Megan Y. Dennis, Daniela C. Soto, Ruta Sahasrabudhe, Gulhan Kaya, Telomere-to-telomere assembly of a com- Josh Quick, Nicholas J. Loman, Nadine Holmes, Matthew Loose, Urvashi Surti, plete human X chromosome. Nature Rosa ana Risques, Tina A. Graves Lindsay, RobertE Fulton, Ira Hall, Benedict Paten, https://doi.org/10.1038/s41586-020-2547-7 Kerstin Howe, Winston Timp, Alice Young, James C. Mullikin, Pavel A. Pevzner, (2020). Jennifer L. Gerton, Beth A. Sullivan, EvanL E. Eichler & Adam M. Phillippy C This is a PDF fle of a peer-reviewedI paper that has been accepted for publication. Although unedited, the Tcontent has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text andR fgures will undergo copyediting and a proof review before the paper is published in its fnal form.
    [Show full text]
  • Prognostic Significance of TIMP-1 in Non-Small Cell Lung Cancer
    ANTICANCER RESEARCH 31: 4031-4038 (2011) Prognostic Significance of TIMP-1 in Non-small Cell Lung Cancer MARTIN PESTA1, VLASTIMIL KULDA2, RADEK KUCERA1, MILOS PESEK3, JINDRA VRZALOVA1, VACLAV LISKA4, LADISLAV PECEN1, VLADISLAV TRESKA4, JARMIL SAFRANEK4, MARKETA PRAZAKOVA1, ONDREJ VYCITAL4, JAN BRUHA4, LUBOS HOLUBEC5 and ONDREJ TOPOLCAN1 Departments of 1Internal Medicine II and 2Biochemistry, Faculty of Medicine in Pilsen, Charles University in Prague, Czech Republic; 3TRN Clinic, University Hospital and Medical Faculty in Pilsen, Czech Republic; Departments of 4Surgery and 5Oncology, University Teaching Hospital, Pilsen, Czech Republic Abstract. Tissue inhibitor of metalloproteinases 1 (TIMP1) the mortality 48.7/100 000 per year (1). Non-small cell lung regulates not only extracellular matrix catabolism but the cancer (NSCLC) accounts for 80% of all cases (2). major effect in tumor tissue is promotion of cell growth and Although there are tumor markers routinely used for solid anti-apoptotic activity. The aim of our study was to evaluate tumors, some of them having become gold standards (3), plasma TIMP1 levels and tissue TIMP1 mRNA expression as there is still an effort being made to search for new ones. prognostic markers in NSCLC patients. Patients and Tissue inhibitor of metalloproteinases 1 (TIMP1) has been Methods: We studied a group of 108 patients with NSCLC studied intensively over the last ten years and in colorectal who had undergone lung surgery. Estimation of TIMP1 cancer it seems to be promising as a prognostic marker in mRNA was performed by quantitative polymerase chain clinical use (4). A Danish-Australian endoscopy study group reaction (qPCR) and estimation of plasma TIMP1 protein on colorectal cancer detection is trying to use TIMP1 as a using enzyme-linked immunosorbent assay (ELISA).
    [Show full text]
  • Demethylation of TIMP2 and TIMP3 Inhibit Cell Proliferation, Migration and Invasion in Pituitary Adenoma
    Demethylation of TIMP2 and TIMP3 inhibit cell proliferation, migration and invasion in pituitary adenoma Yongdong Yang the Second Aliated Hospital of Guilin Medical University Fanjun Huang the Second aliated Hospital of Guilin Medical University Xiufu Wu the Second aliated Hospital of Guilin Medical University Chunqin Huang the Second aliated Hospital of Guilin Medical University Shenyu Li ( [email protected] ) the second aliated hospital of guilin medical university Research article Keywords: Invasive pituitary adenoma, TIMPs, DNA methylation, 5-AzaC, GH3 Posted Date: October 29th, 2019 DOI: https://doi.org/10.21203/rs.2.15805/v2 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/15 Abstract Background: Pituitary adenoma (PA) is one of the most common intracranial neoplasms. Tissue inhibitors of metalloproteinases (TIMPs) are prognostic biological markers, but their biological roles remains largely unclear in invasive PA. Methods: The promoter methylation status of TIMP2 and TIMP3 genes in invasive PA tissues and cells was measured by methylation-specic polymerase chain reaction (MSP). The expression of TIMP1-3 was validated by quantitative real time PCR and western blot analysis. Overexpression and knockdown of TIMP2 and TIMP3 in GH3 cells were created by transfection of pcDNA3.0 and siRNA against TIMP2 and TIMP3, respectively. Functional experiments in GH3 cells were performed with CCK-8 assay, wound healing assay and transwell assay. Effects of 5- Azacytidene (5-AzaC) on the methylation of TIMP2 and TIMP3 gene, and DNA methyltransferase 1 (DNMT1), DNMT3a and DNMT3b were determined by western blot analysis. Results: We found the expression of TIMP1, TIMP2 and TIMP3 was down-regulated in invasive PA tissues and cells.
    [Show full text]
  • A Rare Penetrant TIMP3 Mutation Confers Relatively Late Onset Choroidal Neovascularisation Which Can Mimic Age-Related Macular D
    Eye (2016) 30, 488–491 © 2016 Macmillan Publishers Limited All rights reserved 0950-222X/16 www.nature.com/eye 1,2 3 3 1,2 CASE SERIES A rare penetrant A Warwick , J Gibson , R Sood and A Lotery TIMP3 mutation confers relatively late onset choroidal neovascularisation which can mimic age-related macular degeneration Abstract world.1 Genetic predisposition is thought to play a role and to date 19 genetic loci have been Purpose To perform a genotype–phenotype correlation for three patients heterozygous for associated at a genome-wide level with an 2 a missense mutation in the tissue inhibitor of increased risk of developing AMD. ’ metalloproteinase 3 (TIMP3) gene. Sorsby s fundus dystrophy (SFD) is a rare autosomal dominant fundus dystrophy caused 1Clinical Neurosciences Methods Retrospective, observational case Research Group, Clinical series. The medical records and photographs by mutations in the tissue inhibitor of TIMP3 3 and Experimental Sciences, were reviewed for three patients diagnosed at metalloproteinase 3 ( ) gene. It shares Faculty of Medicine, the time with neovascular age-related macular similar clinical features with AMD, including University of choroidal neovascularisation (CNV), although Southampton, degeneration (AMD). All were later found to Southampton, UK carry a predicted C113G mutation in the TIMP3 the age of onset is typically younger in the fourth gene, other known mutations in which are decade of life. 2Eye Unit, University associated with Sorsby’sfundusdystrophy. We report the clinical phenotypes of three Southampton NHS Trust, Results All three patients developed drusen patients diagnosed at Southampton Eye Unit Southampton, UK and bilateral choroidal neovascularisation with with bilateral neovascular AMD before the subsequent disciform scarring and atrophy.
    [Show full text]
  • Gene Regulation Underlies Environmental Adaptation in House Mice
    Downloaded from genome.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Research Gene regulation underlies environmental adaptation in house mice Katya L. Mack,1 Mallory A. Ballinger,1 Megan Phifer-Rixey,2 and Michael W. Nachman1 1Department of Integrative Biology and Museum of Vertebrate Zoology, University of California, Berkeley, California 94720, USA; 2Department of Biology, Monmouth University, West Long Branch, New Jersey 07764, USA Changes in cis-regulatory regions are thought to play a major role in the genetic basis of adaptation. However, few studies have linked cis-regulatory variation with adaptation in natural populations. Here, using a combination of exome and RNA- seq data, we performed expression quantitative trait locus (eQTL) mapping and allele-specific expression analyses to study the genetic architecture of regulatory variation in wild house mice (Mus musculus domesticus) using individuals from five pop- ulations collected along a latitudinal cline in eastern North America. Mice in this transect showed clinal patterns of variation in several traits, including body mass. Mice were larger in more northern latitudes, in accordance with Bergmann’s rule. We identified 17 genes where cis-eQTLs were clinal outliers and for which expression level was correlated with latitude. Among these clinal outliers, we identified two genes (Adam17 and Bcat2) with cis-eQTLs that were associated with adaptive body mass variation and for which expression is correlated with body mass both within and between populations. Finally, we per- formed a weighted gene co-expression network analysis (WGCNA) to identify expression modules associated with measures of body size variation in these mice.
    [Show full text]
  • Influence of LPS, TNF, TGF-ß1 and IL-4 on the Expression of Mmps, Timps and Selected Cytokines in Rat Synovial Membranes Incubated in Vitro
    127-137.qxd 18/11/2010 09:29 Ì ™ÂÏ›‰·127 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 27: 127-137, 2011 127 Influence of LPS, TNF, TGF-ß1 and IL-4 on the expression of MMPs, TIMPs and selected cytokines in rat synovial membranes incubated in vitro ANNA HYC, ANNA OSIECKA-IWAN, JUSTYNA NIDERLA-BIELINSKA and STANISLAW MOSKALEWSKI Department of Histology and Embryology, Medical University of Warsaw, Chalubinskiego 5 St., PL02-004 Warsaw, Poland Received July 30, 2010; Accepted September 28, 2010 DOI: 10.3892/ijmm.2010.550 Abstract. Synovial membranes are formed by four main Introduction types of cells, i.e. fibroblasts, macrophages, epitheliocytes and adipocytes. To study the combined effect of various The synovial membrane defined in anatomy textbooks as the factors on these cell populations, synovial membranes vascular connective tissue which produces the synovial fluid dissected from rat knee joints were incubated in control (1) is composed of the synovial lining and the subsynovium medium or medium with lipopolysaccharide (LPS), TNF, (2). The synovial lining, also called the synovial intima (3), TGF-ß1 or IL-4 for 12 h. LPS stimulated TNF secretion and consists of macrophage-like type A cells and fibroblast-like both agents stimulated secretion of IL-6. TGF-ß1 slightly B cells (4-6). It is supported by the highly vascularized increased IL-6 secretion. LPS increased the mRNA levels of subsynovium, consisting of loose alveolar tissue, dense fibrous IL-6, IL-1ß, TGF-ß1, MMP1a, MMP1b, MMP3, MMP9, tissue and fat pad (2). MMP13, MMP14, TIMP1 and TIMP3 while the mRNA Most of the studies on the cells present in the synovial levels of MMP2, TIMP2 and TIMP4 were significantly membrane deal with the cells forming the synovial lining decreased.
    [Show full text]
  • Changes in Gene and Protein Expression of Metalloproteinase-2 and -9 and Their Inhibitors TIMP2 and TIMP3 in Different Parts of Fluoride-Exposed Rat Brain
    International Journal of Molecular Sciences Article Changes in Gene and Protein Expression of Metalloproteinase-2 and -9 and Their Inhibitors TIMP2 and TIMP3 in Different Parts of Fluoride-Exposed Rat Brain Agnieszka Łukomska 1 , Irena Baranowska-Bosiacka 2, Karolina Dec 3, Anna Pilutin 4, Maciej Tarnowski 5 , Karolina Jakubczyk 3 , Wojciech Zwierełło˙ 1 , Marta Skórka-Majewicz 1 , Dariusz Chlubek 2 and Izabela Gutowska 1,* 1 Department of Medical Chemistry, Pomeranian Medical University, Powsta´nców Wlkp. 72 Av., 70-111 Szczecin, Poland; [email protected] (A.Ł.); [email protected] (W.Z.);˙ [email protected] (M.S.-M.) 2 Department of Biochemistry, Pomeranian Medical University, Powsta´nców Wlkp. 72 Av., 70-111 Szczecin, Poland; [email protected] (I.B.-B.); [email protected] (D.C.) 3 Department of Human Nutrition and Metabolomic, Pomeranian Medical University, Broniewskiego 24 Str., 71-460 Szczecin, Poland; [email protected] (K.D.); [email protected] (K.J.) 4 Department of Histology and Embryology, Pomeranian Medical University, Powsta´nców Wlkp. 72 Av., 70-111 Szczecin, Poland; [email protected] 5 Department of Physiology, Pomeranian Medical University, Powsta´nców Wlkp. 72 Av., 70-111 Szczecin, Poland; [email protected] * Correspondence: [email protected] Abstract: Fluoride (F) exposure decreases brain receptor activity and neurotransmitter production. Citation: Łukomska, A.; A recent study has shown that chronic fluoride exposure during childhood can affect cognitive func- Baranowska-Bosiacka, I.; Dec, K.; tion and decrease intelligence quotient, but the mechanism of this phenomenon is still incomplete. Pilutin, A.; Tarnowski, M.; Jakubczyk, Extracellular matrix (ECM) and its enzymes are one of the key players of neuroplasticity which is es- K.; Zwierełło,˙ W.; Skórka-Majewicz, sential for cognitive function development.
    [Show full text]
  • Expression of the ETS Transcription Factor ELF3 in the Retinal Pigment Epithelium
    Expression of the ETS Transcription Factor ELF3 in the Retinal Pigment Epithelium Andrew Ian Jobling,1 Zhiping Fang,1 Daniela Koleski,2 and Martin James Tymms1,2 PURPOSE. The ETS family of transcription factors regulate sev- he retinal pigment epithelium (RPE) is a monolayer of cells eral critical cellular functions. They have also been implicated Tbordered basally by the choriocapillaris and apically by the in invertebrate ocular development. This work was undertaken distal tips of the photoreceptors. It constitutes part of the to determine whether epithelium-specific ETS transcription blood–retinal barrier and as such controls the access of serum- factors are expressed in the retinal pigment epithelium and to based factors to the neural retina.1 In addition to this role, the investigate the possible role of these factors in retinal diseases monolayer is involved in the oxidation of retinol, isomerization such as age-related macular degeneration. of the retinoids and phagocytosis of shed photoreceptor outer segments.2–4 Because the pigment epithelium is critical to METHODS. The expression of the epithelial ETS transcription retinal function, factors that regulate RPE gene expression not factors ELF5, ESE3, and ELF3 was assessed by RT-PCR in the only affect tissue homeostasis, but may also have a role in human RPE cell lines D407 and hTERT-RPE1. The full-length Ј disease. coding sequence of rat Elf3 was isolated with 3 rapid ampli- Transcription factors are known to regulate gene expres- fication of cDNA ends (RACE) and degenerative primers, and sion by binding directly to promoter sites within DNA or to its expression was determined in various rat tissues, by RT-PCR other transcription factors.
    [Show full text]
  • Theranostics TIMP3 Expression Associates with Prognosis In
    Theranostics 2019, Vol. 9, Issue 22 6676 Ivyspring International Publisher Theranostics 2019; 9(22): 6676-6689. doi: 10.7150/thno.34020 Research Paper TIMP3 expression associates with prognosis in colorectal cancer and its novel arylsulfonamide inducer, MPT0B390, inhibits tumor growth, metastasis and angiogenesis Han-Li Huang1,2, Yi-Min Liu1, Ting-Yi Sung2, Tsui-Chin Huang3, Ya-Wen Cheng3, Jing-Ping Liou1,4,, Shiow-Lin Pan1,2,3, 1. TMU Biomedical Commercialization Center, Taipei Medical University, Taipei 11031, Taiwan 2. Ph.D Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan. 3. Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan. 4. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan. Corresponding authors: Shiow-Lin Pan, Ph.D. Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan. E-mail: [email protected]. Phone: 886-2-27361661 ext 7671. Jing-Ping Liou, Ph.D. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. No. 250, Wuxing St., Taipei 11031, Taiwan. E-mail address: [email protected]. Phone: 886-2-27361661 ext 6130 © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2019.02.12; Accepted: 2019.07.31; Published: 2019.09.18 Abstract Tissue inhibitors of metalloproteinase 3 (TIMP3) are a major endogenous inhibitor of matrix metalloproteinase (MMPs) that inhibit tumor growth, invasion, metastasis and angiogenesis.
    [Show full text]