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The Effect of Glycosylation on the Biological Activity of Eotaxin and Related Chemokines

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The Effect of Glycosylation on the Biological Activity of Eotaxin and Related Chemokines The effect of glycosylation on the biological activity of eotaxin and related chemokines A thesis submitted for the degree of Doctor of Philosophy University of London by Lee. G. Bodman B.Sc. (Hons) Leukocyte Biology Section Biomedical Sciences Division Sir Alexander Fleming Building Imperial College South Kensington London SW7 2AZ 2004 For my parents 2 Acknowledgements I would like to thank my co-supervisor Dr Dolores Conroy for her unfailing support and excellent teaching over the past years. I would like to thank my co-supervisor Professor Timothy J Williams for enabling me to carry out my PhD in his department, and for his constant encouragement and ideas. This work would not have been possible without the financial assistance of Pfizer (MA, USA) and I am indebted to them for their support. I wish to acknowledge Dr Leonora Bishop for initially recognising my potential and recruiting me for this PhD project. I thank Dr Mike Shelley at Velindre Hospital for allowing me to spend two months within his laboratory and stimulating my interest in medical research. I would also like to thank all the other members of the Imperial College who have helped me along the way particularly: Dr Pete Jose for his words of wisdom (especially regarding the state of Welsh rugby). Dr James Pease (Jimbo) for his encouragement (despite his incredibly poor jokes), Paul (Psuedo) Cameron and James (MQ) Hingston for making my time in London even more enjoyable particularly during the Clayponds years. Louise Jopling (now Dr Joppers aka Mrs Temple) for being such a great friend and supporting me all the way. Mrs Joy Dexter for all her help and assistance whilst I was writing up. Last, but by no means least, I would like to thank Kathy and my family (Mum, Dad, Mark & Carrie-Ann) for pushing me on when times were difficult. 3 Abstract Eotaxin, a C-C chemokine, has been identified as an important mediator of eosinophil trafficking. Glycosylation of guinea pig eotaxin, which occurs on the naturally produced protein, has been shown, using intravital microscopy, to be essential for the recruitment of eosinophils from the guinea pig mesenteric microvasculature. In contrast, recruitment of eosinophils in response to intradermally injected eotaxin was independent of glycosylation. Since eotaxin was applied topically to the surface of the mesentery these observations suggested that glycosylation was necessary for the movement of the chemokine through the surface mesothelial layer. An in vitro chemotaxis assay was set up using freshly isolated guinea pig mesentery in a microBoyden chamber and chemotaxis of eosinophils across this tissue was compared to a polycarbonate filter. Both glycosylated guinea pig and human eotaxin induced a marked chemotaxis of guinea pig and human eosinophils, respectively, across the guinea pig mesentery. In contrast, the non-glycosylated variants showed no chemotactic activity. In contrast, both of the variants induced a similar degree of eosinophil migration across a polycarbonate filter. To determine whether a chemoattractant gradient across the guinea pig mesentery could be established by both the glycosylated and non-glycosylated variants of eotaxin, the flux of the chemokine from the bottom wells to the upper wells of the chemotaxis chamber was measured by ELISA. The glycosylated, but not the non-glycosylated, eotaxin was transported rapidly through the mesentery reaching a near maximal concentration at 60 minutes. The flux of both variants across the polycarbonate filter was indistinguishable. Using confocal microscopy techniques, the presence of glycosylated eotaxin within the mesenteric tissue could be visualised. The non- glycosylated eotaxin could only be observed on the outside of the intact mesothelial cell layer. The metabolic inhibitors 2-deoxyglucose (2-DOG) and sodium cyanide (NaCN) inhibited the flux of the glycosylated eotaxin across the guinea pig mesentery suggesting involvement of an active transport system. In addition transcytosis inhibitors 4 such as monensin and filipin inhibited the flux of the glycosylated eotaxin. Transport was not significantly inhibited by EGTA or by a guinea pig only CCR3 antibody. Gall31 _ 3GalNAc was identified as the sugar present on human eotaxin using a plant lectin binding assay. GalNAc, but not GleNAc, inhibited the flux of the glycosylated eotaxin across the mesentery. The flux of the two variants of eotaxin across the guinea pig mesothelium in vivo was investigated. Glycosylated eotaxin variant was detected in the blood 15 minutes following intraperitoneal injection, whereas the non-glycosylated variant was only detected after 120 minutes, possibly resulting from lymphatic clearance. These data suggest that the eotaxin glycosylation is important for its biological activity on the guinea pig mesentery, and that this effect could be mediated by a specific receptor on the mesothelium recognising the carbohydrate, present on glycosylated eotaxin. 5 Content 1 GENERAL INTRODUCTION 19 1.1 THE ROLE OF LEUKOCYTES AND MAST CELLS IN INFLAMMATORY DISEASE 19 1.1.1 Eosinophils 19 1.1.2 T cells 20 1.1.3 Mast cells 21 1.1.4 Basophils 22 1.1.5 Monocytes and macrophages 22 1.1.6 Neutrophils 23 1.2 THE PROCESS OF LEUKOCYTE RECRUITMENT INTO TISSUE 24 1.2.1 Selectins 25 1.2.2 Integrins 25 1.2.3 I.mmun.oglobulin.s 26 1.3 MEDIATORS OF LEUKOCYTE RECRUITMENT 27 1.3.1 Chemokines 27 1.4 CHEMOKINE RECEPTORS 41 1.4.1 The eotaxin receptor: CCR3 42 1.5 FORMATION OF A CHEMOKINE GRADIENT 43 1.5.1 Glycosaminoglycans 43 1.5.2 The Duffy antigen/receptor for chemokines (DARC) 45 1.6 GLYCOSYLATION 46 1.6.1 Sequence motifs for glycosylation 46 1.6.2 Lepi.dopteron insect cell lines 47 1.6.3 Post-translational modification and cytokine biological activity 48 1.6.4 Eotaxin and glycosylation 49 1.7 PREVIOUS WORK THAT HAS LED UP TO THE PROJECT 50 1.8 THE MESENTERY AND MESOTHELIAL CELLS 51 1.8.1 Mediators released from mesothelial cells 51 1.8.2 Adhesion molecules 52 1.9 HYPOTHESIS OF THIS THESIS 53 2 MATERIALS AND METHODS 61 2.1 MATERIALS 61 2.1.1 Animals 61 2.1.2 General Reagents 61 2.1.3 Special Reagents 62 2.1.4 General. Buffers 63 2.1.5 ELBA Buffers 63 2.1.6 Antibodies 63 2.1.7 Chemokines 64 2.1.8 Other chemoattractants 65 2.2 METHODS 66 6 2.2.1 Gated Auto Fluoresce Scatter Assay (GAFS) 66 2.2.2 Chemotaxis 67 2.2.3 The Flux Assay 69 2.2.4 In vivo study 70 2.2.5 Enzyme Linked Immunosorbent Assay (ELTSA) 71 2.2.6 Protease Activity 74 2.2.7 Identification of the glycosylation present on chemokines 75 2.2.8 Glycosamin.oglycan competition assay 77 2.2.9 SDS-PAGE 77 2.2.10 Confocal microscopy 78 2.2.11 Preparation of mesentery for electron microscopy 79 2.3 STATISTICAL ANALYSIS OF DATA 79 3 COMPARISON OF THE EOSINOPHIL CHEMOATTRACTANT ACTIVITIES OF NATURALLY AND SYNTHETICALLY PRODUCED GUINEA PIG EOTAXIN 87 3.1 DETERMINATION OF THE .IN VIVO EOSINOPHIL RECRUITMENT ACTIVITY OF GLYCOSYLATED NATURAL AND NON-GLYCOSYLATED SYNTHETIC GUINEA PIG EOTAXIN USING INTRAVITAL MICROSCOPY 88 3.1.1 Cell adherence to the mesenteric venule wall 88 3.1.2 Cell migration from the mesenteric venule into the connective tissue 88 3.2 M IN LABELLED EOSINOPHIL MIGRATION INTO THE GUINEA PIG SKIN FOLLOWING INTRADERMAL INJECTION OF GUINEA PIG EOTAXIN 89 3.3 DETERMINATION OF THE MOLECULAR MASS DIFFERENCES BETWEEN THE GLYCOSYLATED NATURAL GUINEA PIG EOTAXIN VARIANTS AND NON-GLYCOSYLATED SYNTHETIC GUINEA PIG EOTAXIN 89 3.3.1 Time of flight mass spectroscopy 89 3.3.2 SDS-PAGE 89 3.4 DETERMINATION OF THE CHEMOTACTIC ACTIVITY OF GLYCOSYLATED AND NON- GLYCOSYLATED GUINEA PIG EOTAXIN ACROSS THE ISOLATED GUINEA PIG MESENTERY • 90 3.5 GUINEA PIG EOTAXIN FLUX ACROSS THE GUINEA PIG MESENTERY 91 3.6 SUMMARY OF RESULTS 93 3.7 DISCUSSION 106 4 DETERMINATION OF THE BIOLOGICAL ACTIVITY OF GLYCOSYLATED HUMAN EOTAXIN 112 4.1 HUMAN EOTAXIN DOES NOT INDUCE GUINEA PIG EOSINOPHILS TO MIGRATE ACROSS A POLYCARBONATE FILTER 113 4.2 A COMPARISON OF THE CHEMOTACTIC ACTIVITY OF GLYCOSYLATED AND NON- GLYCOSYLATED HUMAN EOTAXIN VARIANTS FOR HUMAN EOSINOPHILS ACROSS A GUINEA PIG MESENTERY AND POLYCARBONATE FILTER 113 4.3 HUMAN EOSINOPHIL SHAPE CHANGE INDUCED BY GLYCOSYLATED AND NON- GLYCOSYLATED HUMAN EOTAXIN VARIANTS 114 4.4 THE TRANSPORT OF HUMAN EOTAXIN ACROSS THE GUINEA PIG MESENTERY 114 7 4.4.1 Measurement of the flux of human eotaxin across an isolated guinea pig mesentery and a polycarbonate filter 114 4.4.2 Effect of glycosylated human eotaxin on the flux of glycosylated guinea pig eotaxin across the guinea pig mesentery 115 4.4.3 Effect of glycosylated guinea pig eotaxin on the flux of glycosylated human eotaxin across the guinea pig mesentery 115 4.5 THE BINDING AFFINITY OF GLYCOSYLATED AND NON-GLYCOSYLATED HUMAN EOTAXIN FORMS TO GLYCOSAMINOGLYCANS 116 4.6 ROLE OF MESOTI-IELIAL PROTEASES ON THE MOVEMENT OF GLYCOSYLATED HUMAN EOTAXIN ACROSS THE GUINEA PIG MESENTERY 116 4.6.1 Effect of protease inhibitors on the flux of glycosylated and non- glycosylated human eotaxin 117 4.6.2 Determining the activity of mesentery endoproteases on glycosylated and non-glycosylated human eotaxin 117 4.7 MEASUREMENT OF DIPEPTIDYLPEPTIDASE IV (CD26) ACTIVITY IN THE GUINEA PIG MESENTERY 118 4.8 FLUX OF GLYCOSYLATED AND NON-GLYCOSYLATED HUMAN EOTAXIN ACROSS. THE GUINEA PIG MESENTERY IN VIVO 118 4.9 SUMMARY OF RESULTS 119 4.10 DISCUSSION 136 5 IDENTIFICATION OF TIIE SA.CCHARIDE ON HUMAN EOTAXIN AND THE ROLE OF THE GLYCOSYLATION IN RELATION TO TRANSPORT ACROSS THE GUINEA PIG MESENTERY 147 5.1 IDENTIFICATION OF THE CARBOHYDRATE STRUCTURE ON GLYCOSYLATED HUMAN EOTAXIN 147 5.1.1 Detection of the carbohydrate structure present on glycosylated human eotaxin148 5.2 THE EFFECT OF THE PLANT LECTINS PNA AND WGA ON THE TRANSPORT OF HUMAN EOTAXIN ACROSS THE GUINEA PIG MESENTERY 148 5.3 THE EFFECT OF SACCHARIDES ON THE FLUX OF HUMAN EOTAXIN ACROSS THE ISOLATED GUINEA PIG MESENTERY 149 5.3.1 The effect of the rnonoaccharides Gal.NAe and GleNAC on the flux of glycosylated human eotaxin across the guinea pig mesentery 149 - 5.3.2 The effect of the disaccharide Ga1131.3GalNAc, asialofetuin and fetuin on the flux of glycosylated human eotaxin.
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