Mast cell migration to Th2 stimulated airway smooth muscle from asthmatics. 2006

A Sutcliffe, and D Kaur, and S Page, and L Woodman, and C L Armour, and M Baraket, and P Bradding, and J M Hughes, and C E Brightling
Institute for Lung Health, Department of Infection, University of Leicester, Leicester, UK.

BACKGROUND Mast cell microlocalisation within the airway smooth muscle (ASM) bundle is an important determinant of the asthmatic phenotype. We hypothesised that mast cells migrate towards ASM in response to ASM derived chemokines. METHODS Primary ASM cultures from subjects with and without asthma were stimulated with interleukin (IL)-1beta, IL-4, and IL-13 alone and in combination. Mast cell chemotaxis towards these ASM supernatants was investigated, and the chemotaxins mediating migration by using specific blocking antibodies for stem cell factor (SCF) and the chemokine receptors CCR3, CXCR1, 3 and 4 as well as the Gi inhibitor pertussis toxin and the tyrosine kinase inhibitor genistein were defined. The concentrations of CCL11, CXCL8, CXCL10, TGF-beta, and SCF in the supernatants were measured and the effect of non-asthmatic ASM supernatants on the mast cell chemotactic activity of asthmatic ASM was examined. RESULTS Human lung mast cells and HMC-1 cells migrated towards Th2 stimulated ASM from asthmatics but not non-asthmatics. Mast cell migration was mediated through the combined activation of CCR3 and CXCR1. CCL11 and CXCL8 expression by ASM increased markedly after stimulation, but was similar in those with and without asthma. ASM supernatants from non-asthmatics inhibited mast cell migration towards the asthmatic ASM supernatant. CONCLUSIONS Th2 stimulated ASM from asthmatics is chemotactic for mast cells. Non-asthmatic ASM releases a mediator or mediators that inhibit mast cell migration towards stimulated asthmatic ASM. Specifically targeting mast cell migration into the ASM bundle may provide a novel treatment for asthma.

UI MeSH Term Description Entries
D007378 Interleukins Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. Interleukin
D008407 Mast Cells Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the BASOPHILS, mast cells contain large amounts of HISTAMINE and HEPARIN. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the STEM CELL FACTOR. Basophils, Tissue,Basophil, Tissue,Cell, Mast,Cells, Mast,Mast Cell,Tissue Basophil,Tissue Basophils
D009130 Muscle, Smooth Unstriated and unstriped muscle, one of the muscles of the internal organs, blood vessels, hair follicles, etc. Contractile elements are elongated, usually spindle-shaped cells with centrally located nuclei. Smooth muscle fibers are bound together into sheets or bundles by reticular fibers and frequently elastic nets are also abundant. (From Stedman, 25th ed) Muscle, Involuntary,Smooth Muscle,Involuntary Muscle,Involuntary Muscles,Muscles, Involuntary,Muscles, Smooth,Smooth Muscles
D001980 Bronchi The larger air passages of the lungs arising from the terminal bifurcation of the TRACHEA. They include the largest two primary bronchi which branch out into secondary bronchi, and tertiary bronchi which extend into BRONCHIOLES and PULMONARY ALVEOLI. Primary Bronchi,Primary Bronchus,Secondary Bronchi,Secondary Bronchus,Tertiary Bronchi,Tertiary Bronchus,Bronchi, Primary,Bronchi, Secondary,Bronchi, Tertiary,Bronchus,Bronchus, Primary,Bronchus, Secondary,Bronchus, Tertiary
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D002633 Chemotaxis The movement of cells or organisms toward or away from a substance in response to its concentration gradient. Haptotaxis
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001249 Asthma A form of bronchial disorder with three distinct components: airway hyper-responsiveness (RESPIRATORY HYPERSENSITIVITY), airway INFLAMMATION, and intermittent AIRWAY OBSTRUCTION. It is characterized by spasmodic contraction of airway smooth muscle, WHEEZING, and dyspnea (DYSPNEA, PAROXYSMAL). Asthma, Bronchial,Bronchial Asthma,Asthmas
D016212 Transforming Growth Factor beta A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGF-beta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. Bone-Derived Transforming Growth Factor,Platelet Transforming Growth Factor,TGF-beta,Milk Growth Factor,TGFbeta,Bone Derived Transforming Growth Factor,Factor, Milk Growth,Growth Factor, Milk
D018418 Th2 Cells A subset of helper-inducer T-lymphocytes which synthesize and secrete the INTERLEUKINS IL-4; IL-5; IL-6; and IL-10. These cytokines influence B-cell development and antibody production as well as augmenting humoral responses. T Helper 2 Cell,T Helper2 Cell,TH-2 Cell,Th2 Cell,Type-2 Helper T Cell,T Helper 2 Cells,T Helper2 Cells,TH-2 Cells,Type-2 Helper T Cells,Cell, T Helper2,Cell, TH-2,Cell, Th2,Cells, T Helper2,Cells, TH-2,Cells, Th2,TH 2 Cell,TH 2 Cells,Type 2 Helper T Cell,Type 2 Helper T Cells

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