Involvement of Bruton's Tyrosine Kinase in FcεRI-dependent Mast Cell Degranulation and Cytokine Production (original) (raw)
Article| April 20 1998
From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
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Daisuke Hata, Yuko Kawakami, Naoki Inagaki, Chris S. Lantz, Toshio Kitamura, Wasif N. Khan, Mari Maeda-Yamamoto, Toru Miura, Wei Han, Stephen E. Hartman, Libo Yao, Hiroichi Nagai, Anne E. Goldfeld, Frederick W. Alt, Stephen J. Galli, Owen N. Witte, Toshiaki Kawakami
From the *Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; the ‡Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502, Japan; the §Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115; the ‖Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115; the **Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the ††Howard Hughes Medical Institute, University of California, Los Angeles, California 90024-1662
Address correspondence to Toshiaki Kawakami, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Phone: 619-558-3500; Fax: 619-558-3526; E-mail: toshi_ [email protected]
1_Abbreviations used in this paper:_ BMMC, bone marrow–derived cultured mast cells; Btk, Bruton's tyrosine kinase; ITAM, immunoreceptor tyrosine–based activation motif; NFAT, nuclear factor of activated T cells; PCA, passive cutaneous anaphylactic; PH, pleckstrin homology; PKC, protein kinase C; PLC, phospholipase C; PTK, protein tyrosine kinase; SCF, stem cell factor; SH, Src homology.
This study was partly supported by National Institutes of Health grants RO1 AI-33617 and RO1 AI-38348 (T. Kawakami) and R37 AI-23990 and RO1 CA-72074 (S.J. Galli) and is Publication No. 147 from the La Jolla Institute for Allergy and Immunology.
Received: October 01 1997
Revision Received: January 02 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
J Exp Med (1998) 187 (8): 1235–1247.
Received:
October 01 1997
Revision Received:
January 02 1998
Citation
Daisuke Hata, Yuko Kawakami, Naoki Inagaki, Chris S. Lantz, Toshio Kitamura, Wasif N. Khan, Mari Maeda-Yamamoto, Toru Miura, Wei Han, Stephen E. Hartman, Libo Yao, Hiroichi Nagai, Anne E. Goldfeld, Frederick W. Alt, Stephen J. Galli, Owen N. Witte, Toshiaki Kawakami; Involvement of Bruton's Tyrosine Kinase in FcεRI-dependent Mast Cell Degranulation and Cytokine Production . _J Exp Med 20 April 1998; 187 (8): 1235–1247. doi: https://doi.org/10.1084/jem.187.8.1235
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We investigated the role of Bruton's tyrosine kinase (Btk) in FcεRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcεRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcεRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcεRI-stimulated btk mutant mast cells. The specificity of these effects of btk mutations was confirmed by the improvement in the ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators. Taken together, these results demonstrate an important role for Btk in the full expression of FcεRI signal transduction in mast cells.
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