Lyn-deficient mice develop severe, persistent asthma: Lyn is a critical negative regulator of Th2 immunity

被引:68
作者
Beavitt, SJE
Harder, KW
Kemp, JM
Jones, J
Quilici, C
Casagranda, F
Lam, E
Turner, D
Brennan, S
Sly, PD
Tarlinton, DM
Anderson, GP
Hibbs, ML [1 ]
机构
[1] Royal Melbourne Hosp, Melbourne Tumour Biol Branch, Ludwig Inst Canc Res, Melbourne, Vic 3050, Australia
[2] Univ Melbourne, Dept Med, Lung Dis Res Grp, Melbourne, Vic, Australia
[3] Univ Melbourne, Dept Pharmacol, Lung Dis Res Grp, Melbourne, Vic, Australia
[4] Royal Melbourne Hosp, Dept Med, Cooperat Res Ctr Chron Inflammatory Dis, Melbourne, Vic, Australia
[5] Univ Western Australia, Ctr Child Hlth Res, Perth, WA 6009, Australia
[6] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Melbourne, Vic, Australia
关键词
D O I
10.4049/jimmunol.175.3.1867
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The etiology of asthma, a chronic inflammatory disorder of the airways, remains obscure, although T cells appear to be central disease mediators. Lyn tyrosine kinase has been implicated as both a facilitator and inhibitor of signaling pathways that play a role in allergic inflammation, although its role in asthma is unclear because Lyn is not expressed in T cells. We show in the present study that Lyn(-/-) mice develop a severe, persistent inflammatory asthma-like syndrome with lung eosinophilia, mast cell hyperdegranulation, intensified bronchospasm, hyper IgE, and Th2-polarizing dendritic cells. Dendritic cells from Lyn(-/-) mice have a more immature phenotype, exhibit defective inhibitory signaling pathways, produce less IL-12, and can transfer disease when adoptively transferred into wild-type recipients. Our results show that Lyn regulates the intensity and duration of multiple asthmatic traits and indicate that Lyn is an important negative regulator of Th2 immune responses.
引用
收藏
页码:1867 / 1875
页数:9
相关论文
共 60 条
  • [21] EISEMAN E, 1992, NATURE, V355, P78
  • [22] PI3K-mediated negative feedback regulation of IL-12 production in DCs
    Fukao, T
    Tanabe, M
    Terauchi, Y
    Ota, T
    Matsuda, S
    Asano, T
    Kadowaki, T
    Takeuchi, T
    Koyasu, S
    [J]. NATURE IMMUNOLOGY, 2002, 3 (09) : 875 - 881
  • [23] Activation of SHIP by NADPH oxidase-stimulated Lyn leads to enhanced apoptosis in neutrophils
    Gardai, S
    Whitlock, BB
    Helgason, C
    Ambruso, D
    Fadok, V
    Bratton, D
    Henson, PM
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (07) : 5236 - 5246
  • [24] Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role of Lyn in the myeloid lineage
    Harder, KW
    Parsons, LM
    Armes, J
    Evans, N
    Kountouri, N
    Clark, R
    Quilici, C
    Grail, D
    Hodgson, GS
    Dunn, AR
    Hibbs, ML
    [J]. IMMUNITY, 2001, 15 (04) : 603 - 615
  • [25] Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1
    Harder, KW
    Quilici, C
    Naik, E
    Inglese, M
    Kountouri, N
    Turner, A
    Zlatic, K
    Tarlinton, DM
    Hibbs, ML
    [J]. BLOOD, 2004, 104 (13) : 3901 - 3910
  • [26] Dysregulated FcεRI signaling and altered Fyn and SHIP activities in Lyn-deficient mast cells
    Hernandez-Hansen, V
    Smith, AJ
    Surviladze, Z
    Chigaev, A
    Mazel, T
    Kalesnikoff, J
    Lowell, CA
    Krystal, G
    Sklar, LA
    Wilson, BS
    Oliver, JM
    [J]. JOURNAL OF IMMUNOLOGY, 2004, 173 (01) : 100 - 112
  • [27] Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity
    Hibbs, ML
    Harder, KW
    Armes, J
    Kountouri, N
    Quilici, C
    Casagranda, F
    Dunn, AR
    Tarlinton, DM
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2002, 196 (12) : 1593 - 1604
  • [28] MULTIPLE DEFECTS IN THE IMMUNE-SYSTEM OF LYN-DEFICIENT MICE, CULMINATING IN AUTOIMMUNE-DISEASE
    HIBBS, ML
    TARLINTON, DM
    ARMES, J
    GRAIL, D
    HODGSON, G
    MAGLITTO, R
    STACKER, SA
    DUNN, ARR
    [J]. CELL, 1995, 83 (02) : 301 - 311
  • [29] Constitutive tyrosine phosphorylation of the inhibitory paired Ig-like receptor PIR-B
    Ho, LH
    Uehara, T
    Chen, CC
    Kubagawa, H
    Cooper, MD
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (26) : 15086 - 15090
  • [30] Janas ML, 1999, J IMMUNOL, V163, P4192