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Some Studies on Histamine Release from Mast Cells

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Some Studies on Histamine Release from Mast Cells SOME STUDIES ON HISTAMINE RELEASE FROM MAST CELLS STIMULATED WITH SOMATOSTATIN AND OTHER SECRETAGOGUES A thesis submitted in partial fulfilment of the requirements of the University of London for the degree of Doctor of Philosophy in the faculty of Science by Tatiana A Kassessinoff The Christopher Ingold Laboratories University College London 20 Gordon Street London WC1H OAJ MAY 1991 ProQuest Number: 10629327 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10629327 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 ABSTRACT A variety of polybasic compounds and neuropeptides release histamine from rat serosal mast cells. In the present study, the effect of somatostatin on different mast cells was examined in detail. In this way, it was hoped to elucidate further the mechanisms involved in the activation of mast cells by polyamines and neuropeptides and the possible importance of the latter effect in allergy and inflammation. Somatostatin was shown to be an effective histamine liberator from rat peritoneal mast cells. The process was non-cytotoxic and resembled that evoked by other polybasic agents such as compound 48/80 and substance P in being extremely rapid, independent of extracellular calcium ions and unaffected by added phospholipids. The release was not inhibited by antagonists of the dextran receptor and was independent of cell-fixed antibody. However, secretion was selectively blocked by antagonists of the purported polyamine receptor, benzylammonium chloride (BAC) and benzyl dimethyltetradecyl ammonium chloride (BDTA), and by the C-terminal octapeptide fragment of substance P SP4.n. Cross- desensitisation was observed between somatostatin and other polyamines but not between the neuropeptide and immunologic stimuli. The effect of somatostatin was species and tissue specific. Rat pleural mast cells responded in similar fashion to those from the peritoneum while the latter cells from the hamster and mouse were considerably less reactive. Tissue mast cells of the rat showed graded responsivity while such cells from the guinea pig, the pig and the human were essentially unreactive. Where studied, the relative responsiveness of different mast cells was mirrored by fluorescence binding studies. Varying concentrations of somatostatin did not strikingly modulate immunologic or pharmacologic histamine release from human basophils or murine mast cells. The precise conditions required for BDTA to act as a selective antagonist of polyamine- induced release were established and detailed studies showed the antagonism to be surmountable. The release induced by somatostatin and other polyamines was inhibited by treatment of the cells with neuraminidase and by pertussis toxin, suggesting that sialic acid may be involved in the binding of such agonists to the cell membrane and that a G-protein(s) may be involved in the transduction mechanism. For Roger and Svetlana ii This work was supported by a special studentship from Fisons pic. iii ACKNOWLEDGEMENTS There are many people whom I would like to thank for their assisstance and contributions, most of whom I hope to have acknowledged in the forthcoming text. I would like to express a very personal thankyou to Dr Derek Banthorpe for all his encouragement and support and to Dr Fred Pearce for his invaluable guidance. iv LIST OF ABBREVIATIONS AA arachidonic acid ADP adenosine diphosphate ATEE N-acetyl-tyrosine ester ATP adenosine triphosphate BAA N-benzoyl-arginine amide BAC benzalkonium chloride BAEE N-benzoyl-arginine-ethyl ester BDTA benzyldimethyltetradecyiammonium chloride BMMC bone marrow-derived mast cell BPB p-bromophenylacyl bromide BSA bovine serum albumin BTEE N-benzoyl-tyrosine-ethyl ester CBP cromolyn binding protein CGRP calcitonin gene-related peptide CMF calcium and magnesium free CTC chlortetracycline CTMC connective tissue mast cell cyclic AMP adenosine 3’,5’-cyclic monophosphate cyclic GMP guanosine 3’,5’-cyclic monophosphate DAG 1,2,-diacylglycerol DDA 2 ’,5 ’-dideoxyadenosine DFP diisopropylfluorophosphate DMSO dimethyl sulphoxide DNP dinitrophenol DSCG disodium cromoglycate ECF-A eosinophil chemotactic factor of anaphylaxis EDTA ethylenediaminetetracetic acid EFS electrical field stimulation ETI 5,8,11 -eicosatriynoic acid ETYA 5,8,11,14-eicosatetraynoic acid FMLP F-met-leu-phe GDP guanosine diphosphate GI gastrointestinal GIP gastric inhibitory peptide GSL glycosphingolipid GTP guanosine triphosphate GTP-Y'S guanosine 5’-0-(3-thiophosphate) HEPES N-2-hydroxyethyl-piperazine-N’-2-ethane sulphonic acid HETE - hydroeicosatetraenoic acid HPETE - hydroperoxyeicosatetraenoic acid HTYA - 5,8,11,14'henicosatetraynoic acid IAP - islet activating protein IgA - immunoglobulin A IgE ' immunoglobulin E IgG ' immunoglobulin G IP - inositol monophosphate IP2 - inositol 1,4-bisphosphate IP3 - inositol 1,4,5-trisphosphate ITYA - 4,7,10,13-icosatetraynoic acid LT - leukotriene lysO'PS - lyso-phosphatidyl serine MMC - mucosal mast cell MT ' methyltransferase NANA - N-acetyl neuraminic acid NANC - noradrenergic norcholinergic NCF - neutrophil chemotactic factor NDGA - nordihydroguairetic acid NK - neurokinin OAG - 1 -oleoyl-2-acetyl'glycerol OPT - O'phthaldialdehyde PAF ' platelet activating factor PC - phosphatidyl choline PE - phosphatidyl ethanolamine PF4 - platelet factor 4 PG - prostaglandin PHI - peptide histidine isoleucine PHM - peptide histidine methionine PI - phosphatidyl inositol PI A - N6' (L-2-phenyl'isopropyl) -adenosine PIP - phosphatidyl inositol monophosphate PIP2 - phosphatidyl inositol 4,5-bisphosphate PM A - phorbobl2'myristateT3'acetate PMN - polymorphonuclear PMSF ' phenylmethylsulphonyl chloride PS - phosphatidyl serine RBL - rat basophilic leukaemia cell RPMC - rat peritoneal mast cell SCG ' sodium cromoglycate SEM - standard error of mean SL' - spin labelled- SP ' substance P SPA ' [D'Pro4,D'Trp7’9’10]'SP4.n SPF ' specific pathogen free SRS'A ' slow reacting substance of anaphylaxis TAME ' N'P'toluenesulphonyharginine methyl ester THIQ ' tetrahydroisoquinoline TLCK ' N-tosyl L-lysine chloromethyl ketone TP A - 12-0'tetradecanoylphorbol' 13-acetate TPC - tetradecylpyridinium chloride TPCK - N-tosyl L-phenylalanine chloromethyl ketone VIP - vasoactive intestinal peptide WE - worm equivalents CONTENTS CHAPTER 1 INTRODUCTION 1.1 The Mast Cell 1 1.1.1 Mast cell derived mediators 1 1.1.1.1 Preformed mediators 1 1.1.1.2 Newly generated mediators 2 1.1.2 Mast cell heterogeneity 3 1.1.3 The IgE receptor 4 1.1.4 Membrane receptor activation 5 1.2 Histamine Secretion 5 1.2.1 Calcium 5 1.2.1.1 Extracellular calcium 7 1.2.1.2 Intracellular calcium 8 1.2.1.3 Membrane bound calcium 8 1.2.1.4 Calcium channels 9 1.2.1.5 Calmodulin 9 1.2.2 Phospholipids 11 1.2.2.1 Phosphatidyl serine 11 1.2.2.2 Phospholipid methylation 12 1.2.2.3 Phosphatidyl inositol turnover 12 1.2.3 Arachidonic acid generation and metabolism 15 1.2.4 Protease activation 17 1.2.5 Cyclic nucleotides 18 1.3 Compound 48/80 21 1.3.1 History 21 1.3.2 Calcium and compound 48/80 21 1.3.3 Arachidonic acid 22 1.3.4 Heterogeneity 23 1.3.5 Phospholipids 24 1.3.6 Binding studies 25 1.4 Neuropeptides and the Immune Response 26 1.4.1 Modulation of Immunity and hypersensitivity by sensory neuropeptides 26 1.4.1.1 Distribution of neuropeptides 27 1.4.1.2 Regulation of leucocyte function by somatostatin and substance P 28 1.4.1.3 A model for neurogenic inflammation 29 1.4.1.4 Capsaicin 31 1.4.1.5 Substance P 31 1.5 The Role of Mast Cells in Neurogenic Inflammation 32 1.5.1 Histamine release from mast cells 33 viii 1.5.2 Peptide antagonists 36 1.6 Neuropeptides and Airway Disease 37 1.7 Tissue and Species Selectivity of neuropeptide-mast cell interactions 39 1.8 Aims of the present work 41 CHAPTER 2 MATERIALS AND METHODS 2.1 Materials 43 2.1.1 Tissue and cell sources 43 2.1.1.1 Animals 43 2.1.1.2 Human tissue 43 2.1.2 Buffers 43 2.1.3 Secretagogues 43 2.1.3.1 Immunologic stimuli 43 2.1.3.2 Poiyamine and peptide stimuli 43 2.1.3.3 Other stimuli 45 2.1.4 Inhibitors 45 2.1.5 Enzymes 45 2.1.6 Phospholipids 45 2.1.7 Immunofluorescence materials 46 2.1.8 Other materials 46 2.2 Methods 46 2.2.1 Isolation of histaminocytes 46 2.2.1.1 Murine peritoneal mast cells 46 2.2.1.2 Rat pleural mast cells 47 2.2.1.3 Tissue mast cells 47 2.2.1.4 Human basophil leucocytes 47 2.2.2 Purification of mast cells 47 2.2.3 Metachromatic staining with toluidine blue 48 2.2.4 Sensitization of animals 48 2.2.4.1 Sensitization of rats 48 2.2.4.2 Sensitization of guinea pigs 49 2.2.5 Preparation of reaction agents 49 2.2.5.1 Water soluble agents 49 2.2.5.2 Non-water soluble agents 49 2.2.6 Histamine release experiments 50 2.2.6.1 General procedure 50 2.2.6.2 Addition of phospholipids 51 2.2.6.3 Somatostatin as an inhibitor 51 2.2.7 Histamine assay 51 2.2.7.1 Manual spectrofluorometric assay 51 22.12 Automated assay of histamine 52 2.2.8 Statistical analysis of results 53 ix 2.2.9 Schild Plots 53 2.2.10 Immunofluorescence of mast cells 54 CHAPTER 3 SOME CHARACTERISTICS OF HISTAMINE RELEASE FROM RAT PERITONEAL
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