title: The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils.
abstract: The function of the kinase Btk in neutrophil activation is largely unexplored. Here we found that Btk-deficient neutrophils had more production of reactive oxygen species (ROS) after engagement of Toll-like receptors (TLRs) or receptors for tumor-necrosis factor (TNF), which was associated with more apoptosis and was reversed by transduction of recombinant Btk. Btk-deficient neutrophils in the resting state showed hyperphosphorylation and activation of phosphatidylinositol-3-OH kinase (PI(3)K) and protein tyrosine kinases (PTKs) and were in a 'primed' state with plasma membrane-associated GTPase Rac2. In the absence of Btk, the adaptor Mal was associated with PI(3)K and PTKs at the plasma membrane, whereas in control resting neutrophils, Btk interacted with and confined Mal in the cytoplasm. Our data identify Btk as a critical gatekeeper of neutrophil responses.
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Honda
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kano
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.forename: Eun-Sung
authors.initials: ES
authors.lastname: Kim
authors.forename: Sang-Kyou
authors.initials: SK
authors.lastname: Lee
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D017209:Apoptosis / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D049449:Luminescence; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D017382:Reactive Oxygen Species; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human