Mast Cell Biology: Contemporary and Emerging Topics

Mast Cell Biology

ADVA V NCES IN EXPERIMENTA T L MEDICINE AND BIOLOGY Editorial Board: NATHAN A BACK, State University of New York at Buffalo IRUN U R. COHEN, The Weizmann Institute of Science ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research JOHN D. LAMBRIS, University of Pennsylvania RODOLFO PAOLETTI, University of Milan

Recent Volumes in this Series Volume 708 INVERTEBRATE IMMUNITY Kenneth Söderhäll Volume 709 HISTAMINE IN INFLAMMATION Robin L. Thurmond Volume 710 RECENT ADVANCES ON MODEL HOSTS Eleftherios Mylonakis Volume 711 EPIGENETIC CONTRIBUTIONS IN AUTOIMMUNE DISEASE Esteban Ballestar Volume 712 CYSTEINE PROTEASES OF PATHOGENIC ORGANISMS Mark W. Robinson and John P. Dalton Volume 713 CELL FUSION IN HEALTH AND DISEASE, I: CELL FUSION IN HEALTH Thomas Dittmar Volume 714 CELL FUSION IN HEALTH AND DISEASE, II: CELL FUSION IN DISEASE Thomas Dittmar Volume 715 BACTERIAL ADHESION: BIOLOGY, CHEMISTRY AND PHYSICS Dirk Linke and Adrian Goldman Volume 716 MAST CELL BIOLOGY: CONTEMPORARY AND EMERGING TOPICS       

A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher.

Mast Cell Biology Contemporary and Emerging Topics T Edited by      Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA     Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Landes Bioscience

Springer Science+Business Media, LLC Landes Bioscience Copyright ©2011 Landes Bioscience and Springer Science+Business Media, LLC All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing   # $#  %# # "     $    # $      and executed on a computer system; for exclusive use by the Purchaser of the work. Printed in the USA. Springer Science+Business Media, LLC, 233 Spring Street, New York, New York 10013, USA http://www.springer.com Please address all inquiries to the publishers: Landes Bioscience, 1806 Rio Grande, Austin, T Texas 78701, USA Phone: 512/ 637 6050; FAX: 512/ 637 6079 http://www.landesbioscience.com The chapters in this book are available in the Madame Curie Bioscience Database. http://www.landesbioscience.com/curie Mast Cell Biology: Contemporary and Emerging Topics           Landes Bioscience / Springer Science+Business Media, LLC dual imprint / Springer series: Advances in Experimental Medicine and Biology. ISBN: 978-1-4419-9532-2 &# # $#     $# ! #  $     #    $ of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein.

Library of Congress Cataloging-in-Publication Data Library of Congress Cataloging-in-Publication Data

                      p. ; cm. -- (Advances in experimental medicine and biology ; v. 716) Includes bibliographical references and index. ISBN 978-1-4419-9532-2                !  "   and biology ; v. 716. [DNLM: 1. Mast Cells. W1 AD559 v.716 2011 / QS 532.5.C7] QR185.8.M35M363 2011 571.6--dc22 2011003740

DEDICATION A

The editors would like to dedicate this work to the many present and former members of the Laboratory of Allergic Diseases who have contributed to the success of the clinical and basic research programs in the LAD since the inception of the Laboratory in 1995. We feel privileged to have worked with so many talented and enthusiastic fellows, nurses, administrators and senior scientists. A special thanks to Dr. Anthony Fauci, the Director of the National Institute of Allergy and Infectious Diseases who, along with Dr. Tom T Kindt, then the Director of the NIAID Division of Intramural Research, supported the creation of the LAD; and to Dr. Katherine Zoon for her encouragement and support in the contemporary expansion of the clinical research program of the LAD. We are especially indebted to the patients who have participated in clinical research protocols directed at understanding and treating allergic diseases and systemic mast cell disorders.

v

FOREWORD

The editors of this book, Drs. Gilfillan and Metcalfe, have enlisted an outstanding group of investigators to discuss the emerging concepts in mast cell biology with respect to development of these cells, their homeostasis, their activation, as well as their roles in maintaining health on the one hand and on the other, their participation in disease. As noted by several of the contributors, there have been extraordinary advances in our understanding of these phenomena over the past 40 years since the tools became available to analyze these aspects at a molecular level. Initially, this ability was made possible by the use of so-called model systems by which phenomena such as the allergic response involving the IgE-mediated activation of mast cells, and the related basophils, could be investigated. The discovery of a rat mucosal mast cell tumor analog –the “rat basophilic leukemia” (RBL) cells—and the development of lines of IgE myeloma protein producing cell lines, permitted a rigorous analysis of the cellular receptor that triggered the explosive release of a variety of potent mediators. This was soon followed by the initial identification of the proximal post-receptor molecules that were activated when the receptor-bound IgE was aggregated by antigen or bivalent anti-IgE. As knowledge about similar systems expanded, extraordinarily powerful cell biological methods were developed. That knowledge and those methods have been productively applied to analyze those model systems and, increasingly, their normal counterparts in rodent cells and, even more recently, in human cells. At the same time, less reductive more physiological studies have vastly increased our insight into the role mast cells play in a variety of aspects of the immune response. These new insights not only expand our knowledge of cell biology in general but hopefully will be therapeutically applicable. Indeed, almost without exception, the authors of each of the articles in this compendium end their presentations by noting that their studies have helped to define new targets to which drugs could be directed in order to alleviate some of the pathological phenomena that are mediated by mast cells. However, as noted for example in the contribution by Tsai et al, the fact that mast cells have both positive and negative immunomodulatory functions present the challenge of whether such functions can be manipulated for therapeutic ends by suppressing those

vii

viii

FOREWORD

actions that result in disease without interfering with those functions that promote health by enhancing beneficial immune responses. Two recent events underscore this dilemma. On the down side is the case of Alzheimer T disease. It has long been posited that the disease is caused by the accumulation of socalled amyloid beta plaques in the brain. Because gamma secretase is believed to play an important role in formation of the plaque, a drug designed to inhibit the activity of that enzyme was thought to be promising. Indeed, a trial of such a drug, Eli Lilly’s semagacestat, had advanced to a Phase III clinical trial involving some 2600 patients. But in August of this year the multi-million dollar trial had to be abruptly halted when the developing data showed that the drug not only failed to slow progression of the disease, but was associated with a worsening of cognition and the ability to perform the tasks of daily living. On the other hand, a more hopeful conclusion is prompted by a report published that same month by the laboratory of T Tak Mak.1 That group has been studying the MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) -protein serine/ threonine kinases that are activated by ERK K or p38 and which phosphorylate eIF4E, a component involved in the initiation of cap-dependent translation. Surprisingly, they found that Mnk1/2 double knockout mice not only exhibited normal cell growth and development despite an absence of eIF4E phosphorylation, but that the tumorigenesis occurring in a mouse model was suppressed by the loss of Mnk1/2. Furthermore, stable knockdown of Mnk1 in a human glioma cell line resulted in dramatically decreased tumor formation when these cells were injected into athymic nude mice. Thus, their data demonstrate an oncogenic role for Mnk1/2 in tumor development, and highlight these molecules as potential anticancer drug targets that could be inactivated with minimal side effects. Clearly, translating such findings to warrant a clinical trial will require many more steps but it shows that despite the complexity of cellular biochemical pathways it may be possible to pin-point specific components that though participating in normal functions can be dispensed with when they become involved in pathological processes. Many other results from clinical trials of rationally designed therapeutics, some disappointing, others successful such as the inhibitor of the ABL L tyrosine kinase, imatinib (Gleevec®) and the anti-tumor necrosis factor monoclonals infliximab (Remicade®) and adalimumab (Himura®), could be cited. So how realistic are the proposals that our increased insight into mast cell biology can be translated to yield therapeutic benefits? T To state my own cautious optimism in semi-quantitative terms, I believe that whereas our knowledge can be expected to continue to expand exponentially, the applicability of that knowledge will proceed only linearly and with a rather shallow slope. The enormous expense of clinical trials makes it critical that pre-clinical investigations should be exhaustive, and we must be careful not to let those who pay for our research, whether it be the general public or private investors, be encouraged to believe otherwise. Henry Metzger National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health, Bethesda, Maryland, USA  ' *    @    \  +$? ............. 33 +$ ^C¡RI is Dependent on Dose and Antigen Valency V ............ 97 & +`    ;> ............................................................................. 99 + @ + "   #  8Q  J &   &  .......................................................... 100 h 8 j ................................................................................................................. 100 Conclusion and Future Directions.......................................................................................... 103

7. THE MECHANISMS OF EXOCYTOSIS IN MAST CELLS..........................107 Ulrich Blank Abstract..................................................................................................................................... 107 Introduction.............................................................................................................................. 107 Regulated Exocytosis in Mast Cells........................................................................................ 108     ................................................................................... 109 &  ; ;    ...................................................................... 109 Accessory Proteins in Mast Cell Membrane Fusion ..............................................................111    ^ ;   &  $]; & in Mast Cells ..................................................................................................................... 116 Targets of Calcium ................................................................................................................... 117 T Conclusion ................................................................................................................................ 119

8. AN EMERGING ROLE FOR THE LIPID MEDIATOR A SPHINGOSINE-1-PHOSPHATE A IN MAST CELL EFFECTOR R FUNCTION AND ALLERGIC DISEASE...........................123 Ana Olivera and Juan Rivera Abstract..................................................................................................................................... 123 Introduction.............................................................................................................................. 124 S1P P and Its Targets T ................................................................................................................... 124 Regulation and Function of S1P P in Tissues and Circulatory Fluids.................................... 124 & >kqkq* ]    * .............................................................................. 126 S1P P is Generated by Activated Mast Cells............................................................................. 127 Fc¡RI Induces S1p Formation and Export............................................................................ 131 Functions of S1p Receptors in Mast Cell Responses ............................................................ 132 q@  *     ;  *" ...................... 134 *"; # ;]  "; * 8; S1p from a Non-Mast Cell Source........................................................................................................................ 136 Conclusion ................................................................................................................................ 138

xx

CONTENTS

9. DOWN-REGULATION A OF MAST CELL RESPONSES THROUGH ITIM CONTA T INING INHIBITORY RECEPTORS.................................143 Laila Karra and Francesca Levi-Schaffer Abstract..................................................................................................................................... 143 Introduction.............................................................................................................................. 143 Cell Activation .......................................................................................................................... 144  +8k&#  & +## *.............................................................. 144 Activation and Down-Regulation of Mast Cell Responses: General................................... 146 +8; *J +TIM +TAM T i and ITSM.................................................................... 147

 @ +8; *........................................................................... 149 +8; *  & &j & .......................................................................... 155 Conclusion ................................................................................................................................ 156

SECTION IV: MAST CELLS IN HEALTH AND DISEASE 10. THE MAST CELL IN INNATE A AND ADAPTIVE IMMUNITY ..................162 Christopher P. Shelburne and Soman N. Abraham Abstract..................................................................................................................................... 162 Introduction.............................................................................................................................. 162 &  Q     .......................................................................... 163 &   8 ; ;................................................................................ 164 & @+`##;      .................................................................. 169 Mast Cell Modulation of Innate Responses to Infection ...................................................... 170

    _ +##;  + ......................................... 172 Conclusion ................................................................................................................................ 176

qq & $ % +

)%(*$ )&+(%k  IMMUNOMODULATION A ..........................................................................186 Mindy Tsai, Michele Grimbaldeston and Stephen J. Galli Abstract..................................................................................................................................... 186 Introduction.............................................................................................................................. 186 Mouse Models of Mast-Cell Function .................................................................................... 189 Mast Cell Activation ................................................................................................................ 191 Immunomodulatory Effects on Dendritic Cells .................................................................... 193 +###; $  ;#; ....................................................................... 194 Immunomodulatory Functions in Vivo V .................................................................................. 197 ( %" +###; ^   ............................................. 203 Conclusion ................................................................................................................................ 204

CONTENTS

xxi

12. MAST CELL PROTEASES AS PROTECTIVE AND INFLAMMATORY A MEDIATORS A ....................................................212 George H. Caughey Abstract..................................................................................................................................... 212 Introduction.............................................................................................................................. 213 "  @+`##; $............................................................................. 213 @+`##; *     ................................................................. 224 Conclusion ................................................................................................................................ 227

13. MAST CELLS IN LUNG INFLAMMATION A .................................................235 Elena P. Moiseeva and Peter Bradding Abstract..................................................................................................................................... 235 Introduction.............................................................................................................................. 235

  *#   ........................................................................................ 236

   =;  .................................................................................................... 237 Mast Cells in Lung Defense..................................................................................................... 245

      ...................................................................................... 247 Conclusion ................................................................................................................................ 260

qz & $ % +( $%$+ % %$*.........................................270 Domenico Ribatti and Enrico Crivellato Abstract..................................................................................................................................... 270 Introduction.............................................................................................................................. 270 Mast Cells in Experimental Carcinogenesis .......................................................................... 271 Mast Cell Recruitment to Tumor T ............................................................................................ 272 Mast Cells and Immune Tolerance T ......................................................................................... 273

   &# !  =# & ........................................................................... 274  !  ..................................................................................................... 275 Angiogenesis Factors Stored in Mast Cells............................................................................ 277 Mast Cells in Experimental T Tumor Angiogenesis ................................................................. 278 Mast Cells in Human T Tumor Angiogenesis ............................................................................ 278 Drugs Affecting Mast Cell Number........................................................................................ 281 Conclusion ................................................................................................................................ 281

INDEX........................................................................................................................289

ACKNOWLEDGEMENTS

We thank the chapter authors for their dedication in contributing up to date, outstanding manuscripts for Mast Cell Biology: Contemporary and Emerging Topics.

xxiii

SECTION I

INTRODUCTION

CHAPTER R1 MAST CELL BIOLOGY: Introduction and Overview    |  # > $     Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA               

Abstract:

    #      # " %  # $  of atopic disorders and anaphylaxis, on which it has been historically focused. The biochemical and signaling events responsible for the development and regulation of mast cells has been increasingly studied, aided in large part by novel breakthroughs in laboratory techniques used to study these cells. The result of these studies has      #!      # $  #  their overall biology as well as the various disease states that can now be traced to defects in mast cells. This introductory chapter outlines and highlights the various topics of mast cell biology that will be discussed in further detail in subsequent chapters.

INTRODUCTION Mast cells are cells of hematopoietic origin which have gained notoriety over the years for their role as central players in atopic disorders and anaphylaxis. Indeed, it has   # " # $#  #  #  #  #  $    recently that their role in other aspects of health and disease has been fully appreciated. The manifestations of mast cell-driven disease are considered to be a consequence of an inappropriate activation of mast cell immune responses which have evolved to protect the body against a host of pathogens and perhaps toxins. The biochemical processes regulating mast cell development and mast cell activation have been extensively investigated and comprehensively reviewed in recent years. Hence, rather than reviewing these topics at length, in this work we have opted to focus on the emerging concepts in mast cell biology

Mast Cell Biology: Contemporary and Emerging Topics       and Dean D. Metcalfe. ©2011 Landes Bioscience and Springer Science+Business Media. 2

MAST CELL BIOLOGY: INTRODUCTION AND OVERVIEW

3

with regards not only to mast cell development and activation, but also on the newly        ##   * # #  % #!   $   } "   #      %#   $ on these topics. The scope of this effort cannot be all encompassing and accordingly,     $  #        !  *# <      $ #$    # #         To set the stage for the more in depth discussions that follow, we begin by presenting a brief overview of mast cell biology in general, in which we indicate those topics that will be elaborated upon in subsequent chapters.

& $ *(h&= $'$( $%& % )*'+' Mast cells, at least in the human, develop from CD34 /CD117 pluripotent progenitor cells originating in the bone marrow.1 The progression of these cells to fully mature mast cells is dependent on KIT activation which occurs as a consequence of stem cell factor (SCF)-induced KIT dimerization and auto-phosphorylation. Hence, KitW/W-v and KitW-sh/W-sh mice in which surface expression of KIT, or KIT catalytic activity, is defective, have substantially reduced mast cell numbers.2 Nevertheless, whereas human mast cells in culture require SCF for growth, mouse mast cell growth and expansion from bone marrow progenitors can be maintained by IL-3 in the absence of SCF.1 In both the mouse and human, committed bone marrow mast cell progenitors are released into the bloodstream from where they subsequently migrate into the peripheral tissues, during which time they mature and become terminally differentiated under # {$      $ $$$      Metcalfe DD, eds. Mast Cell Biology: Contemporary and Emerging Topics. Austin/New York: Landes Bioscience/Springer Science Business Media; 2011:186-211. 3. Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol Rev 1997; 77(4):1033-1079. ’ `  > $ #         †     @ $ _••“– 117(6):1214-1225; quiz 1226. € †< ' *# #  "             @ † Contemporary and Emerging Topics. Austin/New York: Landes Bioscience/Springer Science Business Media; 2011:107-122.

10

MAST CELL BIOLOGY

• ` * *#      #  { @ ="   _•••– Œ• $ _—^Œ_  ` * \ ^   \  ‚   ‚   $   @ Immunol 2009; 124(4):639-646; quiz 647-638. ’“ & † ˆ! >  ƒ =" Med 1984; 160(1):12-28. 11. Akashi K, Traver D, Miyamoto T et al. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 2000; 404(6774):193-197. 12. Arinobu Y, Iwasaki H, Gurish MF et al. Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proc Natl Acad Sci USA 2005; 102(50):18105-18110. Œ % ="  _••– €’˜€™_’Œ^__ 38. Abonia JP, Austen KF, Rollins BJ et al. Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2. Blood 2005; 105(11):4308-4313. 39. Sonoda T, Ohno T, Kitamura Y. Concentration of mast-cell progenitors in bone marrow, spleen and blood of mice determined by limiting dilution analysis. J Cell Physiol 1982; 112(1):136-140. 40. Gurish MF, Bell AF, Smith TJ et al. Expression of murine beta 7, alpha 4 and beta 1 integrin genes by rodent mast cells. J Immunol 1992; 149(6):1964-1972. 41. Yuan Q, Jiang WM, Hollander D et al. Identity between the novel integrin beta 7 subunit and an antigen found highly expressed on intraepithelial lymphocytes in the small intestine. Biochem Biophys Res Commun 1991; 176(3):1443-1449. 42. Boyce JA, Mellor EA, Perkins B et al. Human mast cell progenitors use alpha4-integrin, VCAM-1 and \ ƒ^ =^  #!   %# #$ !$ #$ $ {%  Blood 2002; 99(8):2890-2896. 43. Berlin C, Berg EL, Briskin MJ et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 1993; 74(1):185-195. ’’    `$#  ~= \ @   †”  ^    $ $ #  \#%  $    !     $ €€—– “˜_™“’“Œ^“’“” 52. Martelli F, Ghinassi B, Lorenzini R et al. Thrombopoietin inhibits murine mast cell differentiation. Stem Cells 2008; 26(4):912-919. 53. Ghinassi B, Zingariello M, Martelli F et al. Increased differentiation of dermal mast cells in mice lacking the Mpl gene. Stem Cells Dev 2009; 18(7):1081-1092. 54. Ammit AJ, Bekir SS, Johnson PR R et al. Mast cell numbers are increased in the smooth muscle of human sensitized isolated bronchi. Am J Respir Crit Care Med 1997; 155(3):1123-1129.  † # @= †  \     ^      % # $  # N Engl J Med 2002; 346(22):1699-1705.

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MAST CELL BIOLOGY

56. Zanini A, Chetta A, Saetta M et al. Chymase-positive mast cells play a role in the vascular component of airway remodeling in asthma. J Allergy Clin Immunol 2007; 120(2):329-333. 57. Ikeda RK, Miller M, Nayar J et al. Accumulation of peribronchial mast cells in a mouse model of ovalbumin   $ #   % { $  $$  ~ ‹$ J Immunol 2003; 171(9):4860-4867. 58. Yu M, Tsai M, Tam SY et al. Mast cells can promote the development of multiple features of chronic asthma in mice. J Clin Invest 2006; 116(6):1633-1641. 59. Dillon SB, MacDonald TT. Limit dilution analysis of mast cell precursor frequency in the gut epithelium of normal and Trichinella spiralis infected mice. Parasite Immunol 1986; 8(5):503-511. 60. Abonia JP, Hallgren J, Jones T et al. Alpha-4 integrins and VCAM-1, but not MAdCAM-1, are essential   $        # { $ † _••“– •—˜™——^€’ “ # † #%  *$ @    ^      !$ {  $  % $       % { @ =" $ _••– ’˜_™__Œ^__€ 62. Gonzalo JA, Lloyd CM, Kremer K L et al. Eosinophil recruitment to the lung in a murine model of allergic { *#   *^ # @ ! €€“– €—˜•™_ŒŒ_^_Œ’ 63. Briskin M, Winsor-Hines D, Shyjan A et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 1997; 151(1):97-110. 64. Xu B, Wagner N, Pham LN et al. Lymphocyte homing to bronchus-associated lymphoid tissue (BALT) is mediated by L-selectin/PNAd, alpha4beta1 integrin/VCAM-1 and LFA-1 adhesion pathways. J Exp Med 2003; 197(10):1255-1267. 65. Oliveira SH, Lukacs NW. Stem cell factor and igE-stimulated murine mast cells produce chemokines (CCL2, @@ƒ” @@ƒ__™  "  #$^# #% $ €—•– _’˜_™””^”—• 20. Tanaka S, Takasu Y, Mikura S et al. Antigen-independent induction of histamine synthesis by immunoglobulin E in mouse bone marrow-derived mast cells. J Exp Med 2002; 196(2):229-235. 21. Kitaura J, Song J, Tsai M et al. Evidence that IgE molecules mediate a spectrum of effects on mast cell survival and activation via aggregation of the FcepsilonRI. Proc Natl Acad Sci USA 2003; 100(22):12911-12916. 22. Yamada N, Matsushima H, Tagaya Y et al. Generation of a large number of connective tissue type mast cells by culture of murine fetal skin cells. J Invest Dermatol 2003; 121(6):1425-1432. _Œ ˆ@ ƒ *   &      †<  †"  $  #   # homeostasis. Nat Immunol 2002; 3:932-939. 67. Maurer M, Tsai M, Metz M et al. A role for Bax in the regulation of apoptosis in mouse mast cells. J Invest Dermatol 2000; 114:1205-1206. 68. Karlberg M, Ekoff M, Labi V et al. Pro-apoptotic Bax is the major and Bak an auxiliary effector in cytokine deprivation-induced mast cell apoptosis. Cell Death Dis 2010;e43. “€   ž ˆ¤@ ƒ ˆ¤‚ ƒ      †^_^ $  ! independently of the cytochrome c/Apaff 1/caspase-9 apoptosome. Nature 2002; 419:634-637. ”•   ž $ * ˆ¤‚ ƒ   ^    ^€   ‹$    " ž    #  " ž      @ƒ   !     mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412. Blood 2007; 109:3031-3041. 103. Cervero C, Escribano L, San Miguel JF et al. Expression of Bcl-2 by human bone marrow mast cells and its overexpression in mast cell leukemia. Am J Hematol 1999; 60:191-195. 104. Baghestanian M, Jordan JH, Kiener HP et al. Activation of human mast cells through stem cell factor receptor (KIT) is associated with expression of bcl-2. Int Arch Allergy Immunol 2002; 129:228-236. 105. Hartmann K, Artuc M, Baldus SE et al. Expression of Bcl-2 and Bcl-xL in cutaneous and bone marrow lesions of mastocytosis. Am J Pathol 2003; 163:819-826. 106. Oltersdorf T, Elmore SW, Shoemaker AR R et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435:677-681. 107. van Delft MF, Wei AH, Mason KD et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and   $  ! † † @# _••’– 279:40328-36. 207. Tovey SC, de SP, Lipp P et al. Calcium puffs are generic InsP3-activated elementary calcium signals and are downregulated by prolonged hormonal stimulation to inhibit cellular calcium responses. J Cell Sci 2001; 114:3979-89. 208. Berridge MJ. Calcium microdomains: organization and function. Cell Calcium 2006; 40:405-12. 209. Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nat Immunol 2008; 9:1215-23. 210. Beaven MA. Our perception of the mast cell from Paul Ehrlich to now. Eur J Immunol 2009; 39:11-25. 211. Hirasawa N, Santini F, Beaven MA. Activation of the mitogen-activated protein kinase/cytosolic phospholipase A2 pathway in a rat mast cell line. Indications of different pathways for release of arachidonic acid and secretory granules. J Immunol 1995; 154:5391-402. 212. Wodnar-Filipowicz A, Moroni C. Regulation of interleukin 3 mRN R A expression in mast cells occurs at the posttranscriptional level and is mediated by calcium ions. Proc Natl Acad Sci USA 1990; 87:777-81. 213. Plaut M, Pierce JH, Watson CJ et al. Mast cell lines produce lymphokines in response to cross-linkage of Fc¡RI or to calcium ionophores. Nature 1989; 339:64-7. 214. Burd PR, Rogers HW, Gordon JR R et al. Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines. J Exp Med 1989; 170:245-57. 215. Thompson HL, Burbelo PD, Yamada Y et al. Mast cells chemotax to laminin with enhancement after IgE-mediated activation. J Immunol 1989; 143:4188-92. 216. Hofstra CL, Desai PJ, Thurmond RL et al. Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. J Pharmacol Exp Ther 2003; 305:1212-21. 217. Benyon RC, Robinson C, Church MK. Differential release of histamine and eicosanoids from human skin mast cells activated by IgE-dependent and non-immunological stimuli. Brit J Pharmacol 1989; 97:898-904. 218. van Haaster CM, Engels W, Lemmens PJ et al. Differential release of histamine and prostaglandin D2 in rat peritoneal mast cells: roles of cytosolic calcium and protein tyrosine kinases. Biochim Biophys Acta 1995; 1265:79-88. 219. Kim TD, Eddlestone GT, Mahmoud SF et al. Correlating Ca2 responses and secretion in individual RBL-2H3 mucosal mast cells. J Biol Chem 1997; 272:31225-9. 220. Chang WC, Di CJ, Nelson C et al. All-or-none activation of CRAC channels by agonist elicits graded responses in populations of mast cells. J Immunol 2007; 179:5255-63.

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