title: Signalling mechanisms regulating the activation of human eosinophils by mast-cell-derived chymase: implications for mast cell-eosinophil interaction in allergic inflammation.
abstract: Allergic diseases such as asthma and allergic dermatitis are associated with the degranulation of mast cells. Chymase, a mast-cell-specific protease, is the major component in mast cell granules that can induce eosinophil infiltration into inflammatory sites. We examined the immunopathological mechanisms for the activation of eosinophils by chymase in allergic inflammation. Cytokines were measured by cytometric bead array Flex Sets multiplex assay using flow cytometry and enzyme-linked immunosorbent assay. Adhesion molecules, migration and intracellular signalling pathways were assessed by flow cytometry, Boyden chamber assay and Western blot, respectively. Chymase suppressed the apoptosis of eosinophils and induce the release of the cytokine interleukin-6 (IL-6) and chemokines CXCL8, CCL2 and CXCL1 by eosinophils dose-dependently. It also up-regulated the surface expression of adhesion molecule CD18 and stimulated the chemokinetic migration of eosinophils. The expressions of adhesion molecules, cytokines and chemokines, and chemokinetic migration were differentially regulated by the activation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, Akt, Janus-activated kinase and nuclear factor-kappaB pathways. Chymase therefore plays a pivotal immunological role in the interaction between mast cells and eosinophils in allergic diseases such as allergic dermatitis by inducing adhesion molecule-mediated chemokinetic migration and inflammatory cytokines and chemokines of eosinophils, through multiple intracellular signalling molecules and transcription factor. Our results therefore provide a further biochemical basis for the pathogenesis of allergic inflammation consequent on the interaction between mast cells and eosinophils, and give insight for the development of new therapies.
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. ck-wong@cuhk.edu.hk
authors.forename: Chun K
authors.initials: CK
authors.lastname: Wong
authors.forename: Sinnie S M
authors.initials: SS
authors.lastname: Ng
authors.forename: Samantha W M
authors.initials: SW
authors.lastname: Lun
authors.forename: Ju
authors.initials: J
authors.lastname: Cao
authors.forename: Christopher W K
authors.initials: CW
authors.lastname: Lam
mesh_terms: D018821:CD18 Antigens / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D053818:Chymases / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D004804:Eosinophils / Q000276:immunology*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D016207:Cytokines; D016328:NF-kappa B; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D053818:Chymases
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