title: Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production.
abstract: We investigated the role of Bruton's tyrosine kinase (Btk) in FcepsilonRI-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 FcepsilonRI-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 FcepsilonRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcepsilonRI-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 FcepsilonRI signal transduction in mast cells.
authors.affiliation: Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hata
authors.forename: Y
authors.initials: Y
authors.lastname: Kawakami
authors.forename: N
authors.initials: N
authors.lastname: Inagaki
authors.forename: C S
authors.initials: CS
authors.lastname: Lantz
authors.forename: T
authors.initials: T
authors.lastname: Kitamura
authors.forename: W N
authors.initials: WN
authors.lastname: Khan
authors.forename: M
authors.initials: M
authors.lastname: Maeda-Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Miura
authors.forename: W
authors.initials: W
authors.lastname: Han
authors.forename: S E
authors.initials: SE
authors.lastname: Hartman
authors.forename: L
authors.initials: L
authors.lastname: Yao
authors.forename: H
authors.initials: H
authors.lastname: Nagai
authors.forename: A E
authors.initials: AE
authors.lastname: Goldfeld
authors.forename: F W
authors.initials: FW
authors.lastname: Alt
authors.forename: S J
authors.initials: SJ
authors.lastname: Galli
authors.forename: O N
authors.initials: ON
authors.lastname: Witte
authors.forename: T
authors.initials: T
authors.lastname: Kawakami
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001854:Bone Marrow Cells; D015550:Cell Degranulation; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006636:Histamine Release; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D010323:Passive Cutaneous Anaphylaxis / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017455:Receptors, IgE / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D017455:Receptors, IgE; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse