title: Prevention of F-actin assembly switches the response to SCF from chemotaxis to degranulation in human mast cells.
abstract: Following antigen/IgE-mediated aggregation of high affinity IgE-receptors (FcεRI), mast cells (MCs) degranulate and release inflammatory mediators leading to the induction of allergic reactions including anaphylaxis. Migration of MCs to resident tissues and sites of inflammation is regulated by tissue chemotactic factors such as stem cell factor (SCF (KIT ligand)). Despite inducing similar early signaling events to antigen, chemotactic factors, including SCF, produce minimal degranulation in the absence of other stimuli. We therefore investigated whether processes regulating MC chemotaxis are rate limiting for MC mediator release. To investigate this issue, we disrupted actin polymerization, a requirement for MC chemotaxis, with latrunculin B and cytochalasin B, then examined chemotaxis and mediator release in human (hu)MCs induced by antigen or SCF. As expected, such disruption minimally affected early signaling pathways, but attenuated SCF-induced human mast cell chemotaxis. In contrast, SCF, in the absence of other stimuli, induced substantial degranulation in a concentration-dependent manner following actin disassembly. It also moderately enhanced antigen-mediated human mast cell degranulation which was further enhanced in the presence of SCF. These observations suggest that processes regulating cell migration limit MC degranulation as a consequence of cytoskeletal reorganization.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. daniel.smrz@lfmotol.cuni.cz
authors.forename: Daniel
authors.initials: D
authors.lastname: Smrž
authors.forename: Geethani
authors.initials: G
authors.lastname: Bandara
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beaven
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
mesh_terms: D000199:Actins / Q000276:immunology / Q000378:metabolism*; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D018613:Microscopy, Confocal; D019089:Stem Cell Factor / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000199:Actins; D019089:Stem Cell Factor
keywords: Chemotaxis; Degranulation; F-actin; Mast Cell; SCF