IgE Regulation of Mast Cell Growth and Survival

Summary

Principal Investigator: Toshiaki Kawakami
Abstract: High-affinity IgE receptor (FcepsilonRI)-mediated mast cell activation is thought to be critical to the pathogenesis of asthma and other allergic diseases and the host defense against certain parasites. Recently, we have found that mouse mast cell survival and growth are promoted by monomeric IgE binding to FcepsilonRI. Monomeric IgE does not promote DNA synthesis but suppresses the apoptosis induced by growth factor deprivation. This anti-apoptotic effect occurs in parallel with IgE-induced increases in FcepsilonRI surface expression but requires the continuous presence of IgE. These and other data have led us to hypothesize that monomeric IgE binding to FcepsilonRI promotes mast cell growth by suppressing apoptosis. The signal generated by monomeric IgE binding is distinctly different from those generated by FcepsilonRI cross-linking. The anti-apoptotic process initiated by IgE-bound FcepsilonRI involves accelerated degradation of p75NTR, a pro-apoptotic low-affinity receptor for nerve growth factor and other neurotrophins. In order to expand this hypothesis, 1) we will investigate the in vitro effects of monomeric IgE on the growth and survival of rodent and human mast cells and basophils. In light of our data that IgE on the growth facilitates in vitro differentiation of mouse mast cells, we will investigate the IgE effects on the phenotype and functionality of mast cells generated in the presence of IgE. 2) We will analyze the molecular mechanisms by which monomeric IgE interferes with p75NTR-mediated signaling events during the apoptotic process induced by growth factor deprivation in mast cells. To extend our in vitro observations to in vivo studies, 3) we will investigate in vivo effects of IgE on mast cell/basophil growth and survival. These proposed studies are expected not only to shed novel insight into the IgE-dependent process of mast cell biology but also to provide a theoretical basis for the therapeutic approaches aimed at reducing circulating IgE using anti-IgE mAb or soluble FcepsilonRIalpha to the treatment of asthma and other allergic diseases.
Funding Period: 2002-06-01 - 2007-05-31
more information: NIH RePORT

Top Publications

  1. pmc IgE- and IgE+Ag-mediated mast cell migration in an autocrine/paracrine fashion
    Jiro Kitaura
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10 355 Science Center Dr, San Diego, CA 92121, USA
    Blood 105:3222-9. 2005
  2. ncbi Critical role for mast cell Stat5 activity in skin inflammation
    Tomoaki Ando
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    Cell Rep 6:366-76. 2014
  3. ncbi Phospholipase C-β in immune cells
    Toshiaki Kawakami
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA Laboratory of Allergic Disease, RIKEN Center for Integrative Medical Sciences IMS RCAI, Yokohama 230 0045, Japan Electronic address
    Adv Biol Regul 53:249-57. 2013
  4. pmc Mast cells are required for full expression of allergen/SEB-induced skin inflammation
    Tomoaki Ando
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
    J Invest Dermatol 133:2695-705. 2013
  5. pmc Phospholipase C-β3 regulates FcɛRI-mediated mast cell activation by recruiting the protein phosphatase SHP-1
    Wenbin Xiao
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    Immunity 34:893-904. 2011
  6. pmc Tumor suppression by phospholipase C-beta3 via SHP-1-mediated dephosphorylation of Stat5
    Wenbin Xiao
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    Cancer Cell 16:161-71. 2009
  7. pmc A minor catalytic activity of Src family kinases is sufficient for maximal activation of mast cells via the high-affinity IgE receptor
    Michael Poderycki
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    J Immunol 184:84-93. 2010
  8. pmc Polyclonal IgE induces mast cell survival and cytokine production
    Jun ichi Kashiwakura
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, CA, USA
    Allergol Int 58:411-9. 2009
  9. pmc Pivotal advance: IgE accelerates in vitro development of mast cells and modifies their phenotype
    Jun ichi Kashiwakura
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
    J Leukoc Biol 84:357-67. 2008
  10. pmc The Src family kinase Hck regulates mast cell activation by suppressing an inhibitory Src family kinase Lyn
    Hong Hong
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, CA 92037, USA
    Blood 110:2511-9. 2007

Scientific Experts

  • Toshiaki Kawakami
  • Yuko Kawakami
  • Wenbin Xiao
  • Jiro Kitaura
  • Tomoaki Ando
  • Hong Hong
  • Jun ichi Kashiwakura
  • Mari Maeda-Yamamoto
  • Yoshiaki Tomimori
  • Clifford A Lowell
  • Dianqing Wu
  • Yoshimichi Okayama
  • Kenji Matsumoto
  • Hirotaka Yamashita
  • Siavash Namiranian
  • Colin Jamora
  • Miho Kimura
  • Tatsuya Kinoshita
  • Hajime Nishimoto
  • Michael Poderycki
  • Hiroki Yasudo
  • Stephen J Galli
  • Vaclav Horejsi
  • Chisei Ra
  • Michael Croft
  • Michael Leitges
  • Kentaro Matsuda
  • Michael F Gurish
  • Peisong Gao
  • Axel Roers
  • Tissa R Hata
  • Kathleen C Barnes
  • Kenji Izuhara
  • Nicholas M Rafaels
  • James J Lee
  • Brandon R Dolan
  • Haley Glatthorn
  • Karsten Sauer
  • Joaquin Madrenas
  • Dirk M Zajonc
  • Lothar Hennighausen
  • Keisuke Yuki
  • Hans C Oettgen
  • Masutaka Furue
  • Hiromi Kubagawa
  • Hiromitsu Nakauchi
  • Cyrus C Hsia
  • Akiko Kimura
  • Anargyros Xenocostas
  • Luigi F Bertoli
  • Thomas J Kipps
  • Randall S Davis
  • Hirohisa Saito
  • Shunji Hasegawa
  • Benjamin Caplan
  • Luan A Chau
  • Atsushi Iwama
  • Yuko Kato
  • Bridget S Wilson
  • Ulrich Blank
  • Janet R Pfeiffer
  • Shahram Salek-Ardakani
  • Hiroyuki Tanaka
  • Koichi Nagao
  • Hiroichi Nagai
  • Yu Kawakami
  • Naoki Inagaki
  • Susumu Nakae
  • Sucharita M Dutta
  • Koji Eto
  • Motoyasu Iikura
  • Mindy Tsai
  • Karen G Potter
  • Seung Woo Lee
  • Robert S Mittler
  • Shaun Chung
  • Masaaki Matsumoto
  • Byoung S Kwon
  • Satoshi Nunomura
  • Evelyn W Wang
  • Carl F Ware
  • Adrian M Piliponsky

Detail Information

Publications19

  1. pmc IgE- and IgE+Ag-mediated mast cell migration in an autocrine/paracrine fashion
    Jiro Kitaura
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10 355 Science Center Dr, San Diego, CA 92121, USA
    Blood 105:3222-9. 2005
    ..In mouse experiments, naive mast cells are attracted to IgE, and IgE-sensitized mast cells are attracted to antigen. Therefore, IgE and antigen are implicated in mast cell accumulation at allergic tissue sites with local high IgE levels...
  2. ncbi Critical role for mast cell Stat5 activity in skin inflammation
    Tomoaki Ando
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    Cell Rep 6:366-76. 2014
    ..Therefore, STAT5 regulatory mechanisms in mast cells are important for AD pathogenesis...
  3. ncbi Phospholipase C-β in immune cells
    Toshiaki Kawakami
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA Laboratory of Allergic Disease, RIKEN Center for Integrative Medical Sciences IMS RCAI, Yokohama 230 0045, Japan Electronic address
    Adv Biol Regul 53:249-57. 2013
    ..The SPS complex has important regulatory roles in tumorigenesis and immune cell activation. ..
  4. pmc Mast cells are required for full expression of allergen/SEB-induced skin inflammation
    Tomoaki Ando
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
    J Invest Dermatol 133:2695-705. 2013
    ..Therefore, this clinically relevant model provides mechanistic insights into the pathogenic mechanism of human AD. ..
  5. pmc Phospholipase C-β3 regulates FcɛRI-mediated mast cell activation by recruiting the protein phosphatase SHP-1
    Wenbin Xiao
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    Immunity 34:893-904. 2011
    ..Thus, we have defined a PLC-β3- and SHP-1-mediated signaling pathway for FcɛRI-mediated cytokine production...
  6. pmc Tumor suppression by phospholipase C-beta3 via SHP-1-mediated dephosphorylation of Stat5
    Wenbin Xiao
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    Cancer Cell 16:161-71. 2009
    ..The same mechanism for malignant transformation seems to be operative in other human lymphoid and myeloid malignancies. Thus, PLC-beta3 is likely a tumor suppressor...
  7. pmc A minor catalytic activity of Src family kinases is sufficient for maximal activation of mast cells via the high-affinity IgE receptor
    Michael Poderycki
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    J Immunol 184:84-93. 2010
    ..Furthermore, the data suggest that both positive and negative regulatory functions of Lyn are predominantly carried out by its catalytic activity and not an adaptor function...
  8. pmc Polyclonal IgE induces mast cell survival and cytokine production
    Jun ichi Kashiwakura
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, CA, USA
    Allergol Int 58:411-9. 2009
    ..However, no studies have been performed on the effects of polyclonal IgE molecules. Here, we tested whether polyclonal mouse and human IgE molecules affect survival and cytokine production in mast cells...
  9. pmc Pivotal advance: IgE accelerates in vitro development of mast cells and modifies their phenotype
    Jun ichi Kashiwakura
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
    J Leukoc Biol 84:357-67. 2008
    ..Therefore, our results suggest that monomeric IgEs, especially HC IgEs, not only promote mast cell development but also modulate the mast cell phenotype...
  10. pmc The Src family kinase Hck regulates mast cell activation by suppressing an inhibitory Src family kinase Lyn
    Hong Hong
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, CA 92037, USA
    Blood 110:2511-9. 2007
    ..Thus, this study has revealed a hierarchical regulation among SFK members to fine-tune mast cell activation...
  11. ncbi Dysregulation of Src family kinases in mast cells from epilepsy-resistant ASK versus epilepsy-prone EL mice
    Jiro Kitaura
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    J Immunol 178:455-62. 2007
    ....
  12. pmc Development, migration, and survival of mast cells
    Yoshimichi Okayama
    Research Unit for Allergy Transcriptome, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan
    Immunol Res 34:97-115. 2006
    ..Recent studies also demonstrated that monomeric IgE binding to FcepsilonRI can enhance mast-cell survival. In this review we discuss the factors that regulate mast cell development, migration, and survival...
  13. ncbi IgE regulation of mast cell survival and function
    Toshiaki Kawakami
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, California 92121, USA
    Novartis Found Symp 271:100-7; discussion 108-14, 145-51. 2005
    ..Consistent with receptor aggregation induced by monomeric IgE, other means of receptor aggregation, e.g. IgE+antigen and IgE+anti-IgE, can also induce survival and other events in unique ranges of stimulation intensity...
  14. pmc Regulation of dendritic cell maturation and function by Bruton's tyrosine kinase via IL-10 and Stat3
    Yuko Kawakami
    Divisions of Cell Biology and Molecular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA
    Proc Natl Acad Sci U S A 103:153-8. 2006
    ..These negative regulatory functions of Btk in dendritic cells appear to be mediated mainly through autocrine secretion of IL-10 and subsequent activation of Stat3...
  15. ncbi Monomeric IgE enhances human mast cell chemokine production: IL-4 augments and dexamethasone suppresses the response
    Kentaro Matsuda
    Department of Pathology, Stanford University School of Medicine, CA 94305 5324, USA
    J Allergy Clin Immunol 116:1357-63. 2005
    ..Mouse monoclonal IgE antibodies can promote the survival of mouse bone marrow-derived cultured mast cells and induce the cells to secrete mediators in the absence of known specific antigen...
  16. pmc Positive and negative regulation of mast cell activation by Lyn via the FcepsilonRI
    Wenbin Xiao
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA
    J Immunol 175:6885-92. 2005
    ..Furthermore, Lyn-mediated negative regulation was shown to be exerted via the FcepsilonRI beta-ITAM...
  17. pmc Mast cell survival and activation by IgE in the absence of antigen: a consideration of the biologic mechanisms and relevance
    Toshiaki Kawakami
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA
    J Immunol 175:4167-73. 2005
    ....
  18. pmc Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor
    Hajime Nishimoto
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr, San Diego, CA 92121, USA
    Blood 106:4241-8. 2005
    ..Therefore, FcepsilonRI-inducible 4-1BB plays a costimulatory function together with FcepsilonRI stimulation...
  19. ncbi Regulation of highly cytokinergic IgE-induced mast cell adhesion by Src, Syk, Tec, and protein kinase C family kinases
    Jiro Kitaura
    Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA
    J Immunol 174:4495-504. 2005
    ..Thus, binding of HC IgEs to Fc epsilon RI induces adhesion of mast cells to fibronectin by modulating cellular activation signals in a unique fashion...