Mechanisms of human eosinophil cytokine secretion
Human eosinophils contain within their cytoplasmic granules and secretory vesicles distinct cationic proteins, (ECP, MBP) and multiple other preformed proteins, including diverse cytokines. Mechanisms governing secretion of granule-derived proteins underlie the biologic activities and functions of eosinophils. Compound exocytosis, whereby the entire granule contents are released extracellularly following fusion of granules with the plasma membrane, may occur when eosinophils interact with large targets, such as helminthic parasites, but otherwise is neither commonly observed in vivo nor parsimonious in providing a means to selectively secrete granule-derived cytokines or other proteins. Instead, secretion of granule contents from within eosinophils occurs by piecemeal degranulation (PMD). Electron microscopically documented alterations in granule morphology within eosinophils in tissue sites demonstrate that PMD occurs in vivo. Within granules, there is an extensive network of membranotubular structures. From this network, granule contents can be selectively mobilized into vesicles, both small round vesicles and longer curved tubular structures, that transport proteins for secretion at the plasma membrane. Some proteins, such as MBP, are transported in the fluid phase of vesicles whereas others, as recognized for the cytokine, IL-4, are transported bound to their cognate membrane-inserted receptor. PMD enables differential mobilization and selective secretion of specific eosinophil granule-derived cytokines and proteins in response to varied stimuli. Another mechanism by which granule-derived proteins may be specifically secreted is based on responses of extracellular eosinophil granules. Intact, membrane-bound granules extruded from eosinophils have been recognized in diverse disorders (e.g., asthma, dermatitis). We demonstrated that cell-free eosinophil granules can function as independent secretory organelles capable of responding a cytokine (IFN-gamma), a chemokine (eotaxin-1), and cysteinyl leukotrienes via cognate membrane-expressed receptors, topologically oriented with ligand-binding domains displayed externally on granule membranes. Granule membrane-expressed receptors, coupled to intragranular signaling cascades, stimulate selective, agonist-elicited secretion of ECP and cytokines from within eosinophil granules. Department of Microbiology / NUS Immunology Program Seminar Series .... March 2010 Block MD4, 5 Science Drive 2, SG 117597 :: Tel: 6516 3275 :: Fax: 6776 6872