Tyrosine kinase inhibitors: a new approach for asthma.

The pathogenesis of allergic asthma involves the interplay of inflammatory cells and airway-resident cells, and of their secreted mediators including cytokines, chemokines, growth factors and inflammatory mediators. Receptor tyrosine kinases are important for the pathogenesis of airway remodeling. Activation of epidermal growth factor (EGF) receptor kinase and platelet-derived growth factor (PDGF) receptor kinase leads to hyperplasia of airway smooth muscle cells, epithelial cells and goblet cells. Stimulation of non-receptor tyrosine kinases (e.g. Lyn, Lck, Syk, ZAP-70, Fyn, Btk, Itk) is the earliest detectable signaling response upon antigen-induced immunoreceptor activation in inflammatory cells. Cytokine receptor dimerization upon ligand stimulation induces activation of Janus tyrosine kinases (JAKs), leading to recruitment and phosphorylation of signal transducer and activator of transcription (STAT) for selective gene expression regulation. Activation of chemokine receptors can trigger JAK-STAT pathway, Lck, Fyn, Lyn, Fgr, and Syk/Zap-70 to induce chemotaxis of inflammatory cells. Inhibitors of tyrosine kinases have been shown in vitro to block growth factor-induced hyperplasia of airway-resident cells; antigen-induced inflammatory cell activation and cytokine synthesis; cytokine-mediated pro-inflammatory gene expression in inflammatory and airway cells; and chemokine-induced chemotaxis of inflammatory cells. Recently, anti-inflammatory effects of tyrosine kinase inhibitors (e.g. genistein, tyrphostin AG213, piceatannol, tyrphostin AG490, WHI-P97, WHI-P131, Syk antisense) in animal models of allergic asthma have been reported. Therefore, development of inhibitors of tyrosine kinases can be a very attractive strategy for the treatment of asthma.

[1]  C. Charvet,et al.  Signaling through ZAP-70 is required for CXCL12-mediated T-cell transendothelial migration. , 2002, Blood.

[2]  Christina Bitegye,et al.  Tuning of T Cell Clone Size and Activation Threshold by Control of CD25 Expression through Mitogen-Activated Protein Kinase Pathways , 2002, International Archives of Allergy and Immunology.

[3]  P. Dráber,et al.  Src family‐selective tyrosine kinase inhibitor, PP1, inhibits both FcεRI‐ and Thy‐1‐mediated activation of rat basophilic leukemia cells , 1997, European journal of immunology.

[4]  D. J. Calderwood,et al.  Pyrazolo[3,4-d]pyrimidines containing an extended 3-substituent as potent inhibitors of Lck -- a selectivity insight. , 2002, Bioorganic & medicinal chemistry letters.

[5]  J. Hanke,et al.  Discovery of a Novel, Potent, and Src Family-selective Tyrosine Kinase Inhibitor , 1996, The Journal of Biological Chemistry.

[6]  J. Bonner,et al.  Basic fibroblast growth factor induces expression of the PDGF receptor-alpha on human bronchial smooth muscle cells. , 1996, The American journal of physiology.

[7]  M. Taniguchi,et al.  Effect of Emedastine Difumarate on CC Chemokine-Elicited Eosinophil Migration , 2001, International Archives of Allergy and Immunology.

[8]  P. Howarth,et al.  Expression of c-erbB receptors and ligands in the bronchial epithelium of asthmatic subjects. , 2002, The Journal of allergy and clinical immunology.

[9]  J. Darnell STATs and gene regulation. , 1997, Science.

[10]  A. Kay,et al.  Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. , 2003, American journal of respiratory and critical care medicine.

[11]  Pyrrolo[2,3-d]pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck. , 2002, Bioorganic & medicinal chemistry letters.

[12]  T. Kamata,et al.  T Cell Receptor–Induced Calcineurin Activation Regulates T Helper Type 2 Cell Development by Modifying the Interleukin 4 Receptor Signaling Complex , 2000, The Journal of experimental medicine.

[13]  E. Chilvers,et al.  Phosphatidylinositol 3-kinase mediates mitogen-induced human airway smooth muscle cell proliferation. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[14]  S. Stafford,et al.  Lyn Tyrosine Kinase Is Important for IL-5-Stimulated Eosinophil Differentiation1 , 2002, The Journal of Immunology.

[15]  E. Gelfand,et al.  Development of Eosinophilic Airway Inflammation and Airway Hyperresponsiveness in Mast Cell–deficient Mice , 1997, The Journal of experimental medicine.

[16]  P. Howarth,et al.  Involvement of the epidermal growth factor receptor in epithelial repair in asthma , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  P. Foster,et al.  Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model , 1996, The Journal of experimental medicine.

[18]  J Vestbo,et al.  A 15-year follow-up study of ventilatory function in adults with asthma. , 1998, The New England journal of medicine.

[19]  T. Moninger,et al.  Interleukin-9 induces goblet cell hyperplasia during repair of human airway epithelia. , 2003, American journal of respiratory cell and molecular biology.

[20]  H. Hanafusa,et al.  TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. , 1999, Molecular cell.

[21]  K. Dabbagh,et al.  Protease-Activated Receptor 2 Mediates Eosinophil Infiltration and Hyperreactivity in Allergic Inflammation of the Airway1 , 2002, The Journal of Immunology.

[22]  X. P. Liu,et al.  Treatment of allergic asthma by targeting janus kinase 3-dependent leukotriene synthesis in mast cells with 4-(3', 5'-dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97). , 2000, The Journal of pharmacology and experimental therapeutics.

[23]  K. Robbins,et al.  High-affinity IgE receptor-mediated stimulation of rat basophilic leukemia (RBL-2H3) cells induces early and late protein-tyrosine phosphorylations. , 1992, The Journal of biological chemistry.

[24]  W. Busse,et al.  Interleukin 5 signals through Shc and Grb2 in human eosinophils. , 1998, American journal of respiratory cell and molecular biology.

[25]  J. Cambier,et al.  Tyrosine kinase and CD45 tyrosine phosphatase activity mediate p21ras activation in B cells stimulated through the antigen receptor. , 1994, Journal of immunology.

[26]  J. Martin,et al.  Tyrosine kinase-dependent calcium signaling in airway smooth muscle cells. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[27]  S. Gunst,et al.  Tyrosine phosphorylation of the dense plaque protein paxillin is regulated during smooth muscle contraction. , 1996, The American journal of physiology.

[28]  G. Bren,et al.  Signal transduction pathways triggered by the FcϵRIIb receptor (CD23) in human monocytes lead to nuclear factor-κB activation , 1999 .

[29]  M. Toews,et al.  Synergistic stimulation of airway smooth muscle cell mitogenesis. , 2000, The Journal of pharmacology and experimental therapeutics.

[30]  A. Sharpe,et al.  B7-1 (CD80) and B7-2 (CD86) have complementary roles in mediating allergic pulmonary inflammation and airway hyperresponsiveness. , 2000, American journal of respiratory cell and molecular biology.

[31]  W. Leonard,et al.  Mutation of Jak3 in a Patient with SCID: Essential Role of Jak3 in Lymphoid Development , 1995, Science.

[32]  D. Murphy,et al.  Damnacanthal is a highly potent, selective inhibitor of p56lck tyrosine kinase activity. , 1995, Biochemistry.

[33]  R. Martin,et al.  Are eosinophils still important in asthma? , 2001, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[34]  G. Mayr,et al.  Transient Tyrosine Phosphorylation of Human Ryanodine Receptor upon T Cell Stimulation* , 2001, The Journal of Biological Chemistry.

[35]  B. Danforth,et al.  Lysophosphatidic acid upregulates the epidermal growth factor receptor in human airway smooth muscle cells. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[36]  G. Trainor,et al.  CCR3 antagonists: a potential new therapy for the treatment of asthma. Discovery and structure-activity relationships. , 2002, Bioorganic & medicinal chemistry letters.

[37]  K. Arai,et al.  Factors affecting the cytokine production of human T cells stimulated by different modes of activation. , 1996, The Journal of allergy and clinical immunology.

[38]  Andre E Nel,et al.  T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. , 2002, The Journal of allergy and clinical immunology.

[39]  S. Hartman,et al.  Terreic acid, a quinone epoxide inhibitor of Bruton's tyrosine kinase. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[40]  P. Vidalain,et al.  CD40 signaling in human dendritic cells is initiated within membrane rafts , 2000, The EMBO journal.

[41]  F. Uckun,et al.  Rational Design and Synthesis of a Novel Anti-leukemic Agent Targeting Bruton′s Tyrosine Kinase (BTK), LFM-A13 [α-Cyano-β-Hydroxy-β-Methyl-N-(2,5-Dibromophenyl)Propenamide]* , 1999, The Journal of Biological Chemistry.

[42]  A. Zlotnik,et al.  The biology of chemokines and their receptors. , 2000, Annual review of immunology.

[43]  T. Mustelin,et al.  T cell antigen receptor-mediated activation of phospholipase C requires tyrosine phosphorylation. , 1990, Science.

[44]  C. Seow,et al.  Piceatannol, a Syk-selective tyrosine kinase inhibitor, attenuated antigen challenge of guinea pig airways in vitro. , 2002, European journal of pharmacology.

[45]  P. Postmus,et al.  Functional and phenotypic differences of monocyte-derived dendritic cells from allergic and nonallergic patients. , 1998, The Journal of allergy and clinical immunology.

[46]  A. Kapp,et al.  Regulation and modulation of eosinophil effector functions , 1999, Allergy.

[47]  M. Gishizky,et al.  SU6656, a Selective Src Family Kinase Inhibitor, Used To Probe Growth Factor Signaling , 2000, Molecular and Cellular Biology.

[48]  S. Galli,et al.  Mast Cells Can Amplify Airway Reactivity and Features of Chronic Inflammation in an Asthma Model in Mice , 2000, The Journal of experimental medicine.

[49]  P. Changelian,et al.  Genetic ablation of the src kinase p59fynT exacerbates pulmonary inflammation in an allergic mouse model. , 2001, American journal of respiratory cell and molecular biology.

[50]  M. Nadler,et al.  Signal transduction by the high-affinity immunoglobulin E receptor Fc epsilon RI: coupling form to function. , 2000, Advances in immunology.

[51]  S. Wenzel,et al.  TGF-β and IL-13 Synergistically Increase Eotaxin-1 Production in Human Airway Fibroblasts1 , 2002, The Journal of Immunology.

[52]  G. Gleich Mechanisms of eosinophil-associated inflammation. , 2000, The Journal of allergy and clinical immunology.

[53]  S. Fagerholm,et al.  Lck tyrosine kinase is important for activation of the CD11a/CD18‐integrins in human T lymphocytes , 2002, European journal of immunology.

[54]  S. Fujieda,et al.  Protein-Tyrosine Kinase Syk Expressed in Human Nasal Fibroblasts and Its Effect on RANTES Production1 , 2001, The Journal of Immunology.

[55]  C. Agustí,et al.  Epidermal growth factor system regulates mucin production in airways. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[56]  S. Pierce,et al.  Signaling through the B cell antigen receptor regulates discrete steps in the antigen processing pathway. , 1998, Cellular immunology.

[57]  Weijia Zhang,et al.  LAB: A new membrane-associated adaptor molecule in B cell activation , 2003, Nature Immunology.

[58]  M. Shibuya,et al.  Genistein, a specific inhibitor of tyrosine-specific protein kinases. , 1987, The Journal of biological chemistry.

[59]  A. Gilfillan,et al.  Temporal regulation of the IgE-dependent 1,2-diacylglycerol production by tyrosine kinase activation in a rat (RBL 2H3) mast-cell line. , 1994, Biochemical Journal.

[60]  S. Mizuno,et al.  Irreversible inhibition of v-src tyrosine kinase activity by herbimycin A and its abrogation by sulfhydryl compounds. , 1989, Biochemical and biophysical research communications.

[61]  E. Fish,et al.  RANTES and MIP-1α Activate Stats in T Cells* , 1998, The Journal of Biological Chemistry.

[62]  J. D. Dal Porto,et al.  B Cell Antigen Receptor Signaling: Roles in Cell Development and Disease , 2002, Science.

[63]  T. Kawakami,et al.  Tyrosine Phosphorylation is Required for Mast Cell Activation by FcεRI Cross-Linking. , 1992 .

[64]  P. Thompson,et al.  Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma. , 2001, The Journal of allergy and clinical immunology.

[65]  A. Ammit,et al.  Human mast cell and airway smooth muscle cell interactions: implications for asthma. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[66]  S. Haeryfar,et al.  Selective pharmacological inhibitors reveal differences between Thy-1- and T cell receptor-mediated signal transduction in mouse T lymphocytes. , 2001, International immunopharmacology.

[67]  N. Yamashita,et al.  Protein Tyrosine Phosphorylation: A Possible Common Signaling Pathway in Human Th1 and Th2 Cell Clones , 1999, International Archives of Allergy and Immunology.

[68]  C. Martínez-A,et al.  Chemokine signaling and functional responses: the role of receptor dimerization and TK pathway activation. , 2001, Annual review of immunology.

[69]  K. Torgersen,et al.  Lck is required for stromal cell-derived factor 1 alpha (CXCL12)-induced lymphoid cell chemotaxis. , 2002, Blood.

[70]  T. Adachi,et al.  The mechanism of IL-5 signal transduction. , 1998, The American journal of physiology.

[71]  F. Tsang,et al.  Inhibitors of tyrosine kinase signaling cascade attenuated antigen challenge of guinea-pig airways in vitro. , 2000, American journal of respiratory and critical care medicine.

[72]  A. Kapp,et al.  Human eotaxin represents a potent activator of the respiratory burst of human eosinophils , 1996, European journal of immunology.

[73]  C. Schindler,et al.  Series Introduction: JAK-STAT signaling in human disease , 2002 .

[74]  J. Nadel,et al.  Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. , 2001, American journal of respiratory and critical care medicine.

[75]  Martin Bachmann,et al.  Disruption of the murine IL-4 gene blocks Th2 cytokine responses , 1993, Nature.

[76]  B. Bay,et al.  Antiinflammatory effects of genistein, a tyrosine kinase inhibitor, on a guinea pig model of asthma. , 2003, American journal of respiratory and critical care medicine.

[77]  A. H. Koh,et al.  Effects of tyrosine kinase inhibitors on antigen challenge of guinea pig lung in vitro. , 1997, The Journal of pharmacology and experimental therapeutics.

[78]  S. Szabo,et al.  Transcriptional regulation of Th1/Th2 polarization. , 2000, Immunology today.

[79]  B. Vargaftig,et al.  Demonstration of the therapeutic potential of non-anaphylactogenic anti-IgE antibodies in murine models of skin reaction, lung function and inflammation. , 1997, International archives of allergy and immunology.

[80]  M. Sears,et al.  Elevated B cells in sputum of asthmatics. Close correlation with eosinophils. , 1996, American journal of respiratory and critical care medicine.

[81]  S. Akira,et al.  Essential role of Stat6 in IL-4 signalling , 1996, Nature.

[82]  J. Ashwell,et al.  Activation of the Lck tyrosine kinase targets cell surface T cell antigen receptors for lysosomal degradation. , 1997, Immunity.

[83]  S. Toyabe,et al.  Specific immunoglobulin E responses in ZAP‐70‐deficient patients are mediated by Syk‐dependent T‐cell receptor signalling , 2001, Immunology.

[84]  J. Warner,et al.  The effect of tyrosine kinase inhibitors on IgE-mediated histamine release from human lung mast cells and basophils , 1998, Inflammation Research.

[85]  Kenneth G. C. Smith,et al.  Inhibition of the B Cell by CD22: A Requirement for Lyn , 1998, The Journal of experimental medicine.

[86]  G. Chrousos,et al.  Decreased steroid responsiveness at night in nocturnal asthma. Is the macrophage responsible? , 2001, American journal of respiratory and critical care medicine.

[87]  S. Latour,et al.  Proximal protein tyrosine kinases in immunoreceptor signaling. , 2001, Current opinion in immunology.

[88]  P. Foster,et al.  Interleukin-5-producing CD4+ T cells play a pivotal role in aeroallergen-induced eosinophilia, bronchial hyperreactivity, and lung damage in mice. , 1998, American journal of respiratory and critical care medicine.

[89]  I. Pavord,et al.  Mast-cell infiltration of airway smooth muscle in asthma. , 2002, The New England journal of medicine.

[90]  I. Reischl,et al.  Molecular consequences of human mast cell activation following immunoglobulin E-high-affinity immunoglobulin E receptor (IgE-FcepsilonRI) interaction. , 1999, Biochemical pharmacology.

[91]  L. Janssen,et al.  Muscarinic excitation-contraction coupling mechanisms in tracheal and bronchial smooth muscles. , 2001, Journal of applied physiology.

[92]  A. Nakao,et al.  Blockade of JAK2 by tyrphostin AG-490 inhibits antigen-induced eosinophil recruitment into the mouse airways. , 2000, Biochemical and biophysical research communications.

[93]  A. Wardlaw,et al.  Eosinophils: biology and role in disease. , 1995, Advances in immunology.

[94]  R. Scheuermann,et al.  Tyrosine kinase activation in the decision between growth, differentiation, and death responses initiated from the B cell antigen receptor. , 2000, Advances in immunology.

[95]  J. Launay,et al.  5-hydroxytryptamine 2B receptor regulates cell-cycle progression: cross-talk with tyrosine kinase pathways. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[96]  L. Martin,et al.  Interleukin-13 induces proliferation of human airway epithelial cells in vitro via a mechanism mediated by transforming growth factor-alpha. , 2001, American journal of respiratory cell and molecular biology.

[97]  M. Ebina,et al.  Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study. , 1993, The American review of respiratory disease.

[98]  P. Burgel,et al.  Human Eosinophils Induce Mucin Production in Airway Epithelial Cells Via Epidermal Growth Factor Receptor Activation1 , 2001, The Journal of Immunology.

[99]  Tatsuya Hayashi,et al.  Thrombin stimulates the expression of PDGF in lung epithelial cells. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[100]  S. Knechtle,et al.  CD28 Ligation Induces Tyrosine Phosphorylation of Pyk2 but Not Fak in Jurkat T Cells* , 1999, The Journal of Biological Chemistry.

[101]  J. Hogg,et al.  Functional significance of increased airway smooth muscle in asthma and COPD. , 1993, Journal of applied physiology.

[102]  C. Payá,et al.  The signal transduction pathway of CD23 (Fc epsilon RIIb) targets I kappa B kinase. , 1999, Journal of immunology.

[103]  C. Martínez-A,et al.  The chemokine SDF‐lα triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[104]  R. Geha,et al.  IgE regulation and roles in asthma pathogenesis. , 2001, The Journal of allergy and clinical immunology.

[105]  R. Homer,et al.  Airway remodeling in asthma. , 1999, The Journal of clinical investigation.

[106]  D. Spina,et al.  Role of cytokines and chemokines in bronchial hyperresponsiveness and airway inflammation. , 2002, Pharmacology & therapeutics.

[107]  A. Ammit,et al.  Activation of K-p21ras and N-p21ras, but not H-p21ras, is necessary for mitogen-induced human airway smooth-muscle proliferation. , 1999, American journal of respiratory cell and molecular biology.

[108]  K. Chung,et al.  Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsìveness, and the late asthmatic response , 2000, The Lancet.

[109]  R. Panettieri,et al.  IL-13 and IL-4 cause eotaxin release in human airway smooth muscle cells: a role for ERK. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[110]  M. Hollenberg,et al.  Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[111]  M. Ebina,et al.  Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack. , 1992, Chest.

[112]  M. Wills-Karp,et al.  Signal Transducer and Activator of Transcription Factor 6 (Stat6)-deficient Mice Are Protected from Antigen-induced Airway Hyperresponsiveness and Mucus Production , 1998, The Journal of experimental medicine.

[113]  E. Fixman,et al.  Src modulates serotonin-induced calcium signaling by regulating phosphatidylinositol 4,5-bisphosphate. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[114]  W. Paul,et al.  An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[115]  Y. Nasuhara,et al.  Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway. , 1998, American journal of respiratory and critical care medicine.

[116]  M. Steinhoff,et al.  Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. , 1998, American journal of physiology. Cell physiology.

[117]  D. Friend,et al.  The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[118]  R. Locksley,et al.  Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity [published erratum appears in J Exp Med 1997 May 5;185(9):1715] , 1996, The Journal of experimental medicine.

[119]  J. Brugge,et al.  Leukocyte protein tyrosine kinases: potential targets for drug discovery. , 1997, Annual review of immunology.

[120]  J. Benovic,et al.  Mechanisms of proliferation synergy by receptor tyrosine kinase and G protein-coupled receptor activation in human airway smooth muscle. , 2000, American journal of respiratory cell and molecular biology.

[121]  J. Votruba,et al.  Effect of protein kinase inhibitors on primary antibody induction in tissue cultures. , 1998, International journal of immunopharmacology.

[122]  B. Ma,et al.  New insights into the pathogenesis of asthma. , 2003, The Journal of clinical investigation.

[123]  S. Rane,et al.  JAKs, STATs and Src kinases in hematopoiesis , 2002, Oncogene.

[124]  M. van de Rijn,et al.  Allergen-induced bronchial hyperreactivity and eosinophilic inflammation occur in the absence of IgE in a mouse model of asthma. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[125]  R. Pauwels,et al.  Attenuation of allergic airway inflammation in IL‐4 deficient mice , 1994, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[126]  J. Cambier New nomenclature for the Reth motif (or ARH1/TAM/ARAM/YXXL) , 1995, Immunology today.

[127]  W. Farrar,et al.  Selective disruption of interleukin 4 autocrine-regulated loop by a tyrosine kinase inhibitor restricts activity of T-helper 2 cells , 2000 .

[128]  Juhana E. Heinonen,et al.  Silencing of Bruton's tyrosine kinase (Btk) using short interfering RNA duplexes (siRNA) , 2002, FEBS letters.

[129]  R. Alon,et al.  The Src Kinase p56 lck Up-regulates VLA-4 Integrin Affinity , 2001, The Journal of Biological Chemistry.

[130]  R. Geahlen,et al.  Visualization of Syk-Antigen Receptor Interactions Using Green Fluorescent Protein: Differential Roles for Syk and Lyn in the Regulation of Receptor Capping and Internalization1 , 2001, The Journal of Immunology.

[131]  D. Corry,et al.  Interleukins-4, -5, and -13: emerging therapeutic targets in allergic disease. , 2002, Pharmacology & therapeutics.

[132]  P. Ricciardi-Castagnoli,et al.  A Critical Role for Syk Protein Tyrosine Kinase in Fc Receptor-Mediated Antigen Presentation and Induction of Dendritic Cell Maturation , 2003, The Journal of Immunology.

[133]  M. Gilchrist,et al.  Aerosolized Syk Antisense Suppresses Syk Expression, Mediator Release from Macrophages, and Pulmonary Inflammation1 , 2000, The Journal of Immunology.

[134]  P. O'Byrne,et al.  Allergen-induced increases in bone marrow T lymphocytes and interleukin-5 expression in subjects with asthma. , 2002, American journal of respiratory and critical care medicine.

[135]  L. Berg,et al.  New insights into the regulation and functions of Tec family tyrosine kinases in the immune system. , 2002, Current opinion in immunology.

[136]  R. Coffman,et al.  A restricted subset of dendritic cells captures airborne antigens and remains able to activate specific T cells long after antigen exposure. , 2002, Immunity.

[137]  T. Huynh,et al.  RANTES Activates Jak2 and Jak3 to Regulate Engagement of Multiple Signaling Pathways in T Cells* , 2001, The Journal of Biological Chemistry.

[138]  C. Martínez-A,et al.  The chemokine monocyte chemotactic protein 1 triggers Janus kinase 2 activation and tyrosine phosphorylation of the CCR2B receptor. , 1998, Journal of immunology.

[139]  P. Foster,et al.  Role of interleukin‐13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma , 2002, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[140]  T. Kawakami,et al.  Early and late events in Fc epsilon RI signal transduction in human cultured mast cells. , 1997, Journal of immunology.

[141]  P. Schwartzberg,et al.  Tec kinases: modulators of lymphocyte signaling and development. , 2001, Current opinion in immunology.

[142]  J. Peterson,et al.  Discovery of 2-phenylamino-imidazo[4,5-h]isoquinolin-9-ones: a new class of inhibitors of lck kinase. , 2002, Journal of medicinal chemistry.

[143]  N. Frossard,et al.  Nerve growth factor and asthma. , 2002, Pulmonary pharmacology & therapeutics.

[144]  A. Levitzki,et al.  Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor , 1996, Nature.

[145]  R. Djukanović,et al.  The contribution of interleukin (IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma. , 2001, American journal of respiratory cell and molecular biology.

[146]  J. Drazen,et al.  Antigen-induced airway hyperresponsiveness, pulmonary eosinophilia, and chemokine expression in B cell-deficient mice. , 1999, American journal of respiratory cell and molecular biology.

[147]  P. Leder,et al.  Targeted Disruption of the Chemokine Eotaxin Partially Reduces Antigen-induced Tissue Eosinophilia , 1997, The Journal of experimental medicine.

[148]  P. Foster,et al.  Integrated Signals Between IL-13, IL-4, and IL-5 Regulate Airways Hyperreactivity , 2000, The Journal of Immunology.

[149]  T. J. Last,et al.  Intracellular localization of tyrosine kinase substrates beneath crosslinked surface immunoglobulins in B cells , 1991, The Journal of experimental medicine.

[150]  C. Lowell,et al.  Fgr Deficiency Results in Defective Eosinophil Recruitment to the Lung During Allergic Airway Inflammation1 , 2002, The Journal of Immunology.

[151]  J. O’Shea,et al.  Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation , 2002, Nature Immunology.

[152]  H. H. Choo,et al.  Inhibitors of the tyrosine kinase signaling cascade attenuated thrombin-induced guinea pig airway smooth muscle cell proliferation. , 2002, Biochemical and biophysical research communications.

[153]  E. Clark,et al.  Functional CD40 ligand expressed by human blood dendritic cells is up-regulated by CD40 ligation. , 1996, Journal of immunology.

[154]  G. Cieslewicz,et al.  The late, but not early, asthmatic response is dependent on IL-5 and correlates with eosinophil infiltration. , 1999, The Journal of clinical investigation.

[155]  K. Umezawa,et al.  Isolation of a novel tyrosine kinase inhibitor, lavendustin A, from Streptomyces griseolavendus. , 1989, Journal of natural products.

[156]  H. Hammad,et al.  The other cells in asthma: dendritic cell and epithelial cell crosstalk. , 2003, Current opinion in pulmonary medicine.

[157]  R. Marthan,et al.  Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells. , 2001, Journal of applied physiology.

[158]  J. Wallace,et al.  Proteinase-activated receptor-2-mediated matrix metalloproteinase-9 release from airway epithelial cells. , 2000, The Journal of allergy and clinical immunology.

[159]  J. Drazen,et al.  Inflammation and airway function in asthma: what you see is not necessarily what you get. , 1998, American journal of respiratory and critical care medicine.

[160]  J. V. Ravetch,et al.  IgG Fc receptors. , 2001, Annual review of immunology.

[161]  C. June,et al.  The protein tyrosine kinase inhibitor herbimycin A, but not genistein, specifically inhibits signal transduction by the T cell antigen receptor. , 1992, International immunology.

[162]  N. Lukacs Role of chemokines in the pathogenesis of asthma , 2001, Nature Reviews Immunology.

[163]  J. Nadel Role of epidermal growth factor receptor activation in regulating mucin synthesis , 2001, Respiratory research.

[164]  S. Isogai,et al.  Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation. , 1998, The Journal of allergy and clinical immunology.

[165]  T. Mosmann,et al.  Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells. , 1999, Journal of immunology.

[166]  J. Ward,et al.  Effects of protein tyrosine kinase inhibitors on contractility of isolated bronchioles of the rat. , 1997, American journal of respiratory cell and molecular biology.

[167]  R. Coffman,et al.  Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. , 1999, Immunity.

[168]  B. Wilson,et al.  Inhibition of mast cell Fc epsilon R1-mediated signaling and effector function by the Syk-selective inhibitor, piceatannol. , 1994, The Journal of biological chemistry.

[169]  M. Gilchrist,et al.  Inhibition of Allergic Inflammation in the Airways Using Aerosolized Antisense to Syk Kinase1 , 2002, The Journal of Immunology.

[170]  Marietta L. Harrison,et al.  Regulation of Signaling in B Cells through the Phosphorylation of Syk on Linker Region Tyrosines , 2002, The Journal of Biological Chemistry.

[171]  S. Durham,et al.  Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. , 1992, The New England journal of medicine.

[172]  R. Wu,et al.  Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. , 2001, American journal of respiratory and critical care medicine.

[173]  S. Akira,et al.  Abrogation of Bronchial Eosinophilic Inflammation and Airway Hyperreactivity in Signal Transducers and Activators of Transcription (STAT)6-deficient Mice , 1998, The Journal of experimental medicine.

[174]  P. Rothman,et al.  JAK-STAT signaling in asthma. , 2002, The Journal of clinical investigation.

[175]  S. French,et al.  Regulation of Activin A Expression in Mast Cells and Asthma: Its Effect on the Proliferation of Human Airway Smooth Muscle Cells1 , 2003, The Journal of Immunology.

[176]  B. Cochran,et al.  Role of the JAK-STAT pathway in PDGF-stimulated proliferation of human airway smooth muscle cells. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[177]  D D Donaldson,et al.  Interleukin-13: central mediator of allergic asthma , 1998 .

[178]  H. Saito,et al.  IL-1 Induced Chemokine Production Through the Association of Syk with TNF Receptor-Associated Factor-6 in Nasal Fibroblast Lines1 , 2001, The Journal of Immunology.

[179]  Y. Rhee,et al.  The involvement of matrix metalloproteinase‐9 in airway inflammation of patients with acute asthma , 2001, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[180]  C. Martínez-A,et al.  CCR7-mediated physiological lymphocyte homing involves activation of a tyrosine kinase pathway. , 2003, Blood.

[181]  G. Canonica,et al.  Human lung myofibroblasts as effectors of the inflammatory process: the common receptor γ  chain is induced by Th2 cytokines, and CD40 ligand is induced by lipopolysaccharide, thrombin and TNF‐α  , 2002 .

[182]  F. Uckun,et al.  Targeting Janus Kinase 3 in Mast Cells Prevents Immediate Hypersensitivity Reactions and Anaphylaxis* , 1999, The Journal of Biological Chemistry.

[183]  S. Stafford,et al.  A novel Lyn-binding peptide inhibitor blocks eosinophil differentiation, survival, and airway eosinophilic inflammation. , 1999, Journal of immunology.

[184]  J. Trevillyan,et al.  Differential inhibition of T cell receptor signal transduction and early activation events by a selective inhibitor of protein-tyrosine kinase. , 1990, Journal of immunology.

[185]  B. Foxwell,et al.  Differential regulation of CD3- and CD28-induced IL-2 and IFN-gamma production by a novel tyrosine kinase inhibitor XR774 from Cladosporium cf. cladosporioides. , 2001, International immunopharmacology.

[186]  C. Agustí,et al.  Platelet-activating factor induces goblet cell hyperplasia and mucin gene expression in airways. , 1998, American journal of respiratory and critical care medicine.

[187]  A. Levitzki,et al.  Tyrosine kinase inhibition: an approach to drug development. , 1995, Science.

[188]  Bernhard Moser,et al.  Lymphocyte traffic control by chemokines , 2001, Nature Immunology.

[189]  D. J. Matthews,et al.  IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. , 2000, Immunity.

[190]  J. Gutiérrez-Ramos,et al.  Eotaxin: from an eosinophilic chemokine to a major regulator of allergic reactions. , 1999, Immunology today.

[191]  A. Sharpe,et al.  Defects in B Lymphocyte Maturation and T Lymphocyte Activation in Mice Lacking Jak3 , 1995, Science.

[192]  W. Busse,et al.  Anti-immunoglobulin E (omalizumab) therapy in allergic asthma. , 2001, American journal of respiratory and critical care medicine.

[193]  P. Howarth,et al.  Basic fibroblast growth factor in asthma: measurement in bronchoalveolar lavage fluid basally and following allergen challenge. , 2001, The Journal of allergy and clinical immunology.

[194]  B. Vargaftig,et al.  What can we learn from murine models of asthma? , 1999, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[195]  J. Black,et al.  Factors controlling smooth muscle proliferation and airway remodelling , 2002, Current Opinion in Allergy and Clinical Immunology.

[196]  T. Suda,et al.  Novel association of the src family kinases, hck and c-fgr, with CCR3 receptor stimulation: A possible mechanism for eotaxin-induced human eosinophil chemotaxis. , 1999, Biochemical and biophysical research communications.

[197]  A. Weiss,et al.  Nocodazole Inhibits Signal Transduction by the T Cell Antigen Receptor* , 1998, The Journal of Biological Chemistry.

[198]  M. Reth,et al.  Monomeric and oligomeric complexes of the B cell antigen receptor. , 2000, Immunity.

[199]  L. Samelson,et al.  Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins. , 2002, Annual review of immunology.