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Celiac Disease and Cholecystokinin Cell Dysfunction

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Celiac Disease and Cholecystokinin Cell Dysfunction Université Catholique de Louvain Faculté de Médecine Service de Gastro-entérologie CELIAC DISEASE AND CHOLECYSTOKININ CELL DYSFUNCTION: A MODEL OF INTERACTION BETWEEN THE DIGESTIVE, ENDOCRINE AND IMMUNE SYSTEMS IN THE GUT. Pierre H. Deprez Thèse présentée en vue de l’obtention du Grade de Docteur en Sciences biomédicales Orientation : Gastro-Entérologie 2003 Promoteur: Professeur André Geubel Université Catholique de Louvain Faculté de Médecine Service de Gastro-entérologie CELIAC DISEASE AND CHOLECYSTOKININ CELL DYSFUNCTION: A MODEL OF INTERACTION BETWEEN THE DIGESTIVE, ENDOCRINE AND IMMUNE SYSTEMS IN THE GUT. Pierre H. Deprez Thèse présentée en vue de l’obtention du Grade de Docteur en Sciences biomédicales Orientation : Gastro-Entérologie 2003 Promoteur: Professeur André Geubel AVANT PROPOS ET REMERCIEMENTS Je souhaite exprimer ma reconnaissance au Professeur M. Crochet, Recteur, au Professeur J-F. Denef, Prorecteur et au Professeur J-J. Rombouts, Doyen de la Faculté de Médecine, pour la qualité de la formation médicale et scientifique qu’ils m’ont permis d’acquérir au sein de l’Université Catholique de louvain. Je remercie tout d’abord mon promoteur, le Professeur A. Geubel pour la confiance qu’il m’a témoignée au sein du service de Gastro-entérologie. Mes études sur les hormones digestives ont débuté dans le laboratoire de Gastro-entérologie sous la supervision des Professeurs Ch. Dive et S. Pauwels. Je leur suis très reconnaissant de m’avoir initié à la recherche fondamentale et de m’avoir fait rencontrer feu le Professeur J. Calam qui m’a accueilli avec enthousiasme dans son équipe au Hammersmith Hospital. L’environnement scientifique qu’il m’a proposé est une expérience inoubliable par la richesse des échanges scientifiques mais aussi personnels. J’y ai bénéficié d’une collaboration fructueuse avec tous les membres du laboratoire: les Docteurs G. Mousouli, H. Hodgson, J. Walters et tout particulièrement le Professeur R. Playford qui m’a apporté une aide appréciable. De retour à l’UCL, mes travaux ont pu progresser grâce au soutien du Professeur P. Mainguet qui m’a aidé à transposer mes travaux à la maladie cœliaque et du Professeur S. Pauwels par ses conseils toujours avisés et son expérience dans le domaine des hormones digestives. Aux laboratoires de Gastro-entérologie et de Médecine Nucléaire, j’ai pu compter sur le soutien attentif de Madame Ch. De Saeger, de Monsieur J-P. Dehennin et de Madame M. Lecroart. La collaboration entretenue tout au long du travail avec le service d’anatomie pathologique, en particulier avec le Professeur J. Rahier et le Docteur Ch. Sempoux, a été à mes yeux des plus enrichissante et fructueuse. Mes remerciements vont également au Président de mon Comité d’Encadrement, le Professeur D. Maiter et les membres non encore cités, dont le Professeur J-Ch. Renaud, pour leurs conseils avisés. Mener en parallèle un travail de recherche scientifique et une activité clinique soutenue n’aurait pas pu être possible sans les encouragements de l’ensemble du service de Gastro-entérologie, en particulier de Yves Horsmans, que je remercie sincèrement de m’avoir poussé à finaliser cette thèse. Etablir une priorité quand on est passionné à la fois par la médecine, les patients, les performances techniques endoscopiques, la recherche clinique, l’enseignement, la défense de la profession de gastro-entérologue et de médecin universitaire fut un véritable challenge. Les années se sont évidemment écoulées depuis mon enthousiasme initial pour la gastrine et la cholécystokinine. Défendre cette thèse aujourd’hui, c’est finalement le résultat d’une démarche personnelle faite de passions multiples qui sont, je l’espère, loin d’être éteintes. Je me dois donc de rendre un hommage tout particulier à Martine, mon épouse, qui a eu le mérite d’user de son intelligence émotionnelle pour me convaincre ces deux dernières années de finaliser ce doctorat avant d’entamer de nouveaux chantiers… Je lui témoigne donc de ma profonde gratitude, ainsi qu’à ma mère qui m’a toujours soutenu contre vents et marées. Je n’oublie certainement pas mes filles, Louise et Pauline, qui ont éprouvé quelques difficultés à accepter que cette thèse accapare leur père mais qui ont continué à m’aider par leur sourire et leurs attentions pendant toute la période de rédaction. TABLE OF CONTENTS Summary . .1 Résumé . .3 Abbreviations . .5 Chapter I Introduction . 7 Chapter II Cholecystokinin . 9 1-General overview . 9 2-Peptide structure . 10 3-Biosynthesis and processing . 11 4-Cellular/molecular mechanisms regulating CCK cell differentiation . 12 5-Cellular/molecular mechanisms regulating CCK gene expression . 13 5.1 CCK gene and promoter . 13 5.2 CCK gene expression and nutrients . .13 5.3 CCK gene expression in STC-1 cell line . .14 5.4 Neuropeptides and PACAP . .14 6-CCK-1 and CCK-2 receptors . 14 7-CCK receptor antagonists . 15 8-Regulation of secretion . 18 8.1 Effects of nutrients on CCK secretion . 19 8.2 Feedback regulation of CCK secretion . 19 8.2.a Feedback regulation in rats . .19 8.2.b CCK releasing peptides . .19 8.2.c Feedback regulation in men . .20 8.2.d Feedback regulation and surgery . .20 8.3 Neural regulation of CCK secretion . 20 8.4 CCK release in the brain . 20 9-Biological functions of CCK in the alimentary tract . 21 9.1 Pancreas . 21 9.1.a Pancreatic secretion . 21 9.1.b Pancreatic growth . .22 9.1.c Regulation of carbohydrate metabolism . .22 9.1.d Clinical impact in pancreatic diseases . .22 9.2 Gallbladder and bile ducts . ..
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