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Somatostatin Receptors and Their Ligands in the Human Immune System

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Somatostatin Receptors and Their Ligands in the Human Immune System SOMATOSTATIN RECEPTORS AND THEIR LIGANDS IN THE HUMAN IMMUNE SYSTEM ISBN 90-77128-06-9 © 2003 V.A.S.H. Dalm No part of this thesis may be reproduced or transmitted in any form by any means electronic or mechanical, including photocopying, recording or any information storage and retrieval system, without the written permission from the publisher (V.A.S.H. Dalm, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands) Printed by: Optima Grafische Communicatie, Rotterdam, The Netherlands SOMATOSTATIN RECEPTORS AND THEIR LIGANDS IN THE HUMAN IMMUNE SYSTEM SOMATOSTATINE RECEPTOREN EN LIGANDEN IN HET HUMANE IMMUUNSYSTEEM PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de Rector Magnificus Prof.dr.ir. J.H. van Bemmel en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 1 oktober 2003 om 15.45 uur door Virgil Alain Silvester Hovestadt Dalm geboren te Dordrecht Promotiecommissie Promotor: Prof.dr. S.W.J. Lamberts Overige leden: Prof.dr. R. Benner Prof.dr. I.P. Touw Prof.dr. E.P. Krenning Co-promotoren: Dr. L.J. Hofland Dr. P.M. van Hagen Paranimfen: Wijnand K. den Dekker, Elisabeth F.C. van Rossum Dit proefschrift is tot stand gekomen binnen de afdeling Inwendige Geneeskunde van de Erasmus Universiteit Rotterdam. Het in dit proefschrift beschreven onderzoek werd financieel ondersteund door de Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), programmasubsidie 903-43-092 (prof.dr. S.W.J. Lamberts). In de drukkosten van dit proefschrift werd bijgedragen door Ipsen Farmaceutica B.V., ZonMw, J. Hurkmans & M. de Jong-Hurkmans. aan mijn ouders aan Roos Publications based on the studies described in the thesis Chapter II Dalm VA, van Hagen PM, van Koetsveld PM, Langerak AW, van der Lely AJ, Lamberts SW and Hofland LJ. 2003 Cortistatin rather than somatostatin as a potential endogenous ligand for somatostatin receptors in the human immune system. J Clin Endocrinol Metab 88(1):270-276 Dalm VA, van Hagen PM, de Krijger RR, Kros JM, van Koetsveld PM, van der Lely AJ, Lamberts SW and Hofland LJ. 2003 Distribution pattern of somatostatin and cortistatin mRNA in human central and peripheral tissues. Submitted Lichtenauer-Kaligis EG, Dalm VA, Oomen SP, Mooij DM, van Hagen PM, Lamberts SW and Hofland LJ. 2003 Differential expression of somatostatin receptor subtypes, somatostatin and cortistatin in human peripheral blood mononuclear cell subsets. Submitted Dalm VA, van Hagen PM, van Koetsveld PM, Achilefu S, Houtsmuller AB, Pols DH, van der Lely AJ, Lamberts SW and Hofland LJ. 2003 Expression of somatostatin, cortistatin and somatostatin receptors in human monocytes, macrophages and dendritic cells. Am J Physiol Endocrinol Metab 285(2):E344-353 Chapter III Ferone D, Pivonello R, van Hagen PM, Dalm VA, Lichtenauer-Kaligis EG, Waaijers M, van Koetsveld PM, Mooij DM, Colao A, Minuto F, Lamberts SW and Hofland LJ. 2002 Quantitative and functional expression of somatostatin receptor subtypes in human thymocytes. Am J Physiol Endocrinol Metab 283(5):E1056-1066 Chapter IV Dalm VA, van Hagen PM and Krenning EP. 2003 The role of octreotide scintigraphy in rheumatoid arthritis and sarcoidosis. Q J Nucl Med in press Dalm VA, Hofland LJ, Mooy CM, Waaijers M, van Koetsveld PM, Langerak AW, Staal FT, van der Lely AJ, Lamberts SW and van Hagen PM. 2003 Somatostatin receptors in malignant lymphomas: targets for radiotherapy? Submitted CONTENTS Chapter I I.1 General introduction 11 I.2 Aim of the thesis 49 Chapter II Somatostatin receptors and their ligands in human immune cells II.1 Cortistatin rather than somatostatin as a potential 53 endogenous ligand for somatostatin receptors in the human immune system II.2 Distribution pattern of somatostatin and cortistatin 71 mRNA in human central and peripheral tissues II.3 Differential expression of somatostatin receptor 79 subtypes, somatostatin and cortistatin in human peripheral blood mononuclear cell subsets II.4 Regulation of the expression of somatostatin, 103 cortistatin and somatostatin receptors in human monocytes, macrophages and dendritic cells II.5 The effects of glucocorticoids on somatostatin 127 receptor expression in human macrophages Chapter III The functional significance of somatostatin receptor expression in human immune cells III.1a Quantitative and functional expression of 137 somatostatin receptor subtypes in human thymocytes III.1b Effects of cortistatin on freshly isolated 159 human thymocytes III.2 cDNA micro-array analysis of gene expression 167 changes induced by octreotide in human macrophages III.3 Macrophage-fibroblast interactions: an in 179 vitro model for sarcoidosis and therapeutical implications for somatostatin analogues? Chapter IV The significance of somatostatin receptor expression in diagnosis and therapy of diseases originating from the human immune system IV.1 The role of octreotide scintigraphy in non- 195 Hodgkin’s and Hodgkin’s lymphomas, rheumatoid arthritis and sarcoidosis IV.2 Somatostatin receptors in malignant lymphomas: 213 targets for radiotherapy ? Chapter V General discussion 231 Chapter VI Summary & Samenvatting 243 Abbreviations 250 Dankwoord 252 Curriculum Vitae 254 Chapter I.1 GENERAL INTRODUCTION General introduction Maintenance of homeostasis is essential for survival of the mammalian organism. For a long time it was believed that the different systems in the human body act independently from each other to achieve this goal. However, during the last decades it has become more evident that the different systems in the human body integrate and regulate different functions in close interaction. Numerous studies have provided evidence that the immune, endocrine and neural systems interact to maintain homeostasis. The first suggestion that neuropeptides and neurohormones might play regulatory roles in the immune system came with the detection of corticotropin (ACTH), which is a peptide hormone, in the immune system (1,2). Since then, expression of various neuroendocrine hormones, neuropeptides and their receptors has been described in cells of the immune system (for a review see: (3-5)). In addition, lymphoid organs are extensively innervated and neuropeptides can reach and might act on lymphocytes and macrophages via this route. On the other hand, expression of cytokines and its receptors, which were thought to be restricted to the immune system, has been described in the neuroendocrine system (3). These findings point to the existence of bi-directional regulatory pathways between the immune and neuroendocrine systems and have led to an increasing number of studies, evaluating neuroendocrine-immune interactions. These interactions are very complex. Many reciprocal interactions are still poorly understood and many mechanisms are still difficult to interpret. However, it has become more evident that the neuroendocrine- immune interactions are very important in maintaining homeostasis and that disturbances in these links may be involved in pathological conditions. For instance, infections are regarded by the neuroendocrine system as stressors and the neuroendocrine system has to maintain homeostasis of the body. Activation of the immune system by an agent not only evokes potential dangers to the agent, but potentially also to the integrity of the host, because overly vigorous responses may kill the host in the process of controlling an infection. Therefore, the neuroendocrine system has to constantly monitor and, if necessary, regulate the immune cell functions. On the other hand, the immune system needs the neuroendocrine system to help determining how to respond in case of an invading agent (6). Any disturbances in the cross-talks between both systems could be very important in the development or maintenance of disease and a clearer understanding of these interactions may have important therapeutical applications. 12 Chapter I.1 Cells of the monocyte lineage: an important cellular component of the immune system In the previous paragraph, the existence of interactions between the neuroendocrine and immune system has been introduced. An important cellular component of the immune system, which is involved in the initial activation (innate immunity), are the cells of the monocyte lineage, i.e. monocytes, macrophages and dendritic cells. These cells play important regulatory roles in human host defense by phagocytosis, cytokine production and antigen presentation. Macrophages were already identified in 1882 as cells, present in loose connective tissue, that were able to phagocytose foreign material (7). In 1972 the mononuclear phagocyte system (MPS) was postulated based on similarities in morphology, function and hematopoietic origin (8). The different tissue macrophages, dendritic cells, the peripheral blood monocytes (which are the common precursors of macrophages and dendritic cells) and their bone marrow precursors are now considered to belong to the MPS (9). Figure 1 shows schematically the development of the different cells from the pluripotent bone marrow stem cells. Figure 1: Development of cells of the monocyte lineage Bone marrow Blood Tissue Macrophage Pluripotent Myeloid stem cell stem cell Monoblast Monocyte Dendritic cell Dendritic cell This figure shows the development of monocytes and its functionally derived cells, macrophages and dendritic cells, from the pluripotent stem cells, originating in the bone marrow. Monocytes that circulate in blood can leave the bloodstream and differentiate in the organs (10). These
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