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The Enzymatic Machinery of Leukotriene Biosynthesis: Studies on Ontogenic Expression, Interactions and Function

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The Enzymatic Machinery of Leukotriene Biosynthesis: Studies on Ontogenic Expression, Interactions and Function Linköping University Medical Dissertations No. 1287 The enzymatic machinery of leukotriene biosynthesis: Studies on ontogenic expression, interactions and function Tobias Strid Division of Cell Biology Department of Clinical and Experimental Medicine Faculty of Health Sciences, Linköping University SE-581 85 Linköping, Sweden www.liu.se © Tobias Strid 2012 Cover: Pixel-inverted scan of LTA4H in situ hybridized mouse e18.5 fetus. Printed by LiU-Tryck, Linköping, Sweden 2012 ISBN: 978-91-7519-987-0 ISSN 0345-0082 Published articles were reprinted with permission from the copyright holder Elsevier Ltd. According to Elsevier’s policy on author postings Research is the act of going up alleys to see if they are blind // Plutarch Supervisor: Faculty opponent: Professor Sven Hammarström Professor Ralf Morgenstern Department of Clinical and Experimental Institute of Environmental Medicine Medicine, Faculty of Health Sciences, Karolinska Institute, Stockholm Linköping University Co-supervisor: Board committee: Dr. Mats Söderström Dr. David Engblom Department of Clinical and Experimental Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Medicine, Faculty of Health Sciences, Linköping University Linköping University Professor Jan Ernerudh Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University Professor Ernst Oliw Department of Pharmaceutical Biosciences Uppsala University Professor Christer Tagesson Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University List of Papers LIST OF PAPERS This thesis is based upon the following papers referred to in the text by roman numerals: I: Strid T., Söderström M., and Hammarström S. (2008) Leukotriene C4 synthase promoter driven expression of GFP reveals cell specificity. Biochem Biophys Res Commun. 366: 80-85. http://www.journals.elsevier.com/biochemical-and-biophysical-research- communications/ II: Strid T., Svartz J., Franck N., Hallin E., Ingelsson B., Söderström M., and Hammarström S. (2009) Distinct parts of leukotriene C4 synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein, Biochem Biophys Res Commun. 381: 518-522. III: Strid T., Karlsson C., Söderström M., Zhang J., Qian H., Sigvardsson M., and Hammarström S. (2009) Fetal hepatic expression of 5-lipoxygenase activating protein is confined to colonizing hematopoietic cells, Biochem Biophys Res Commun. 383: 336-339. IV: Strid T., Sigvardsson M., Karlsson C., Söderström M., Qiang H., and Hammarström S. (2012) Expression of leukotriene biosynthesis proteins in fetal and adult hematopoietic cells and its functional effects on hematopoiesis. Manuscript. I Populärvetenskaplig Sammanfattning POPULÄRVETENSKAPLIG SAMMANFATTNING Leukotriener tillhör gruppen eikosanoider som är biologiskt aktiva substanser bildade från fleromättade fettsyror. De verkar proinflammatoriskt och deltar i utvecklandet av inflammatoriska sjukdomar såsom astma, allergi, hjärtinfarkt och stroke. De bildas genom att enzymet 5-lipoxygenas (5-LO) tillsammans med aktiveringsproteinet FLAP, omvandlar arakidonsyra, till leukotrien A4 (LTA4). FLAP saknar egen enzymatisk aktivitet, och dess roll anses vara att överföra arakidonsyra från fosfolipas A2 till 5-LO. LTA4 är en instabil molekyl som spontant bryts ned om den inte omvandlas till LTB4 av enzymet LTA4 hydrolas eller till LTC4 av LTC4 syntas. Leukotriener bildas runt cellens kärnmembran där FLAP och LTC4S är belägna och dit 5-LO förflyttas i samband med inflammatorisk aktivering av cellen. Vi har studerat proteinerna som möjliggör syntes av LTC4 och visat att FLAP och LTC4S kan binda till varandra genom sina membrangenomträngande delar. Proteinerna binder till 5-LO genom sina vattenlösliga delar som sticker upp ur membranet. De proteiner som behövs för att bilda leukotriener finns i vissa typer av vita blodkroppar. LTA4H finns i de flesta celler medan övriga proteiner finns i betydligt färre celltyper. Vi undersökte LTC4S genens uttryck genom att konstruera en vektor som uttrycker det lätt påvisbara proteinet GFP under reglering av promotorn för LTC4S. Denna vektor gav ett cellspecifikt uttryck liknande det naturliga för LTC4S när vektorn fördes in i olika celltyper. GFP uttrycket ökade av ämnen som tidigare visats stimulera LTC4S. Vektorn är alltså lämplig som rapportör för LTC4S uttryck. II Populärvetenskaplig Sammanfattning DNA från vektorn användes för att ta fram genmodifierade möss som uttrycker GFP som LTC4S markör. Leukotrienbiosyntesproteiners uttryck under fosterutveckling undersöktes med två andra tekniker som specifikt påvisar enskilda proteiners mRNA respektive proteinet självt. Resultaten visade att ett komplett maskineri för leukotriensyntes uttrycks i levern under fosterutvecklingen. Under denna tid sker här blodbildning från celler som koloniserar levern. Vi särskilde olika celltyper i fetal lever genom cellsortering och undersökte vilka som uttryckte mRNA kodande för proteiner viktiga för leukotriensyntes. Störst mängd fanns i mogna myeloida celler, men även i omogna blodceller fann vi FLAP. Detta fick oss att spekulera kring leukotrieners roll i att reglera själva blodbildningen. Vi undersökte detta genom att analysera cellsammansättningen i blod och benmärg från möss som saknar FLAP och leukotrien produktion. Det var tidigare känt att sådana möss har dämpade inflammatoriska svar. Våra resultat visade att förhållandet av B- till T-lymfocyter var lägre hos dessa möss jämfört med kontrolldjur. Resultaten tyder på att leukotriener deltar i reglering av blodcellers differentiering och därmed är möjliga mål vid behandling av sjukdomar som drabbar blodbildningen. II Abstract ABSTRACT Leukotrienes (LTs) are biologically active arachidonic acid (AA) derivatives generated by the 5-lipoxygenase (5-LO) pathway. They are produced by myeloid cells. 5-LO converts AA to LTA4 in cooperation with 5-LO activating protein (FLAP). LTA4 is converted to LTB4, by LTA4-hydrolase (LTA4H) or to LTC4 by LTC4-synthase (LTC4S). LTs act on cells through plasma membrane bound G-protein coupled receptors found on leukocytes, smooth muscle and endothelial cells. We report here protein-protein interactions of proteins involved in LTC4 synthesis. 5-LO interacts with cytosolic domains of the integral membrane proteins FLAP and LTC4S at the nuclear envelope, in addition LTC4S interacts with FLAP through its hydrophobic membrane spanning regions. We constructed an LTC4S promoter controlled GFP reporter vector, displaying cell specific expression and sensitivity to agents known to affect LTC4S expression. The vector was used to create transgenic mice expressing GFP as a reporter for LTC4S. Ontogenic mouse expression studies revealed that the complete LT biosynthesis machinery was present at e11.5 primarily in the hematopoietic cells colonizing the liver. Although mature myeloid cells were the main contributors, a substantial amount of FLAP message was also detected in hematopoietic stem and progenitor cells, indicating possible functions for FLAP in hematopoietic regulation. Functional analyses using FLAP knockout mice suggested fine-tuning roles for LTs during differentiation, primarily along the B-lymphocyte differentiation path. III Abbreviations ABBREVIATIONS LSC, leukemic stem cell LSK, lineage- Sca1+ cKit+ cells AA, arachidonic acid AGM, aorta-gonad-mesonephros LT, leukotriene AP1, activating protein 1 LTA4H, leukotriene A4 hydrolase LTC S, leukotriene C synthase AP2, activating protein 2 4 4 LT-HSC/LSC: long term HSC/LSC BLT1R, leukotriene B4 receptor 1 MAPEG, membrane-associated proteins BLT2R, leukotriene B4 receptor 2 cAMP, cyclic AMP in eicosanoid and glutathione CLP, common lymphoid progenitors metabolism CMP, common myeloid progenitors MAPK, mitogen activated protein kinase COX, cyclooxygenase MEP, megakaryocyte and erythroid progenitor cPLA2, cytosolic phospholipase A2 CysLT, cysteinyl leukotriene mGST, microsomal glutathione S- transferase CysLT1R, CysLT receptor 1 MPP, multipotential progenitor CysLT2R, CysLT receptor 2 DAG, diacyl glycerol MRP1, multidrug resistance associated DHGLA, dihomo-γ-linolenic acid protein 1 eGFP, enhanced green fluorescent MS, multiple sclerosis protein NE, nuclear envelope EPA, eicosapentaenoic acid NK-cell, natural killer cell ER, endoplasmatic reticulum OAG, 1-oleoyl-2-acteyl-sn-glycerol ERK, extracellular regulated kinase PAF, platelet activating factor EX, eoxin PG, prostaglandin FACS, fluorescence-activated cell sorting PI3K, phosphoinositide 3-kinase FLAP, 5-lipoxygenase activating protein PIP2, phosphatidylinositol-2-phosphate FLIM, fluorescence lifetime imaging PKC, protein kinase C microscopy PPARα, peroxisome proliferator- GMLP, granulocyte, macrophage, activated receptor-α lymphoid progenitor PTX, pertussis toxin GMP, granulocyte and macrophage PUFA, polyunsaturated fatty acid progenitor RA, retinoic acid GPCR, G-protein coupled receptor ROS, reactive oxygen spices GSH, reduced glutathione SNP, single nucleotide polymorphism GST, glutathione S-transferase SP1, specificity protein 1 HETE, hydroxyeicosatetraenoic acid SP3, specificity protein 3 HPC, hematopoietic progenitor cell SRS-A, slow reacting substance of HpETE, hydroperoxyeicosatetraenoic anaphylaxis acid STAT3, signal transducer and activator HSC, hematopoietic stem cell of transcription 3 IP3, Inositol tris-phosphate ST-HSC/LSC, short term HSC/LSC ISH, in situ hybridization TGF- β, transforming growth factor β LMPP, lymphoid primed multipotential TPA, 12-O-tetradecanoylphorbol-13- progenitor acetate
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