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Originally published online as doi:10.1189/jlb.1103593 on July 7, 2004

Published online before print July 7, 2004
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(Journal of Leukocyte Biology. 2004;76:876-885.)
© 2004 by Society for Leukocyte Biology

Sorting soluble tumor necrosis factor (TNF) receptor for storage and regulated secretion in hematopoietic cells

Ying Gao*, Markus Hansson*, Jero Calafat{dagger}, Hans Tapper{ddagger} and Inge Olsson*,1

* Departments of Hematology, C14, and
{ddagger} Cell and Molecular Biology, B14, BMC, Lund, Sweden; and
{dagger} The Netherlands Cancer Institute, Amsterdam

1Correspondence: Department of Hematology, C14, BMC, SE-221 84 Lund, Sweden. E-mail: Inge.Olsson{at}hematologi.lu.se

Hematopoietic cells contain secretory lysosomes that degranulate at sites of inflammation. We envisage that secretory granules can act as vehicles for targeting inflammatory sites, including malignancies, and thereafter, locally release therapeutically active agents to these sites. Exogenous proteins, such as the soluble tumor necrosis factor receptor 1 (sTNFR1), have been shown previously to be targeted to secretory lysosomes [1 ]. In this work, we asked whether exogenous, secretory lysosome-targeted proteins were subject to regulated secretion. sTNFR1–transmembrane (tm)–cytosol-sorting signal (Y) and sTNFR1–tm–Y–enhanced green fluorescent protein (egfp) were expressed in rat basophilic leukemia cell clones having different secretory capacities. sTNFR1–tm–Y was targeted directly from the Golgi to secretory lysosomes, followed by generation of membrane-free sTNFR1, whose secretion could be triggered by a Ca2+ ionophore or immunoglobulin E receptor activation. In contrast, sTNFR1–tm–Y–egfp was targeted to the plasma membrane and then subjected to endocytosis and presumably, secretory lysosome targeting, as judged by results from antibody ligation and cell-surface biotinylation. Activation of protein kinase C with phorbol ester promoted ectodomain shedding at the cell surface, resulting in sTNFR1 release from sTNFR1–tm–Y–egfp. These results support a concept for using the storage organelles of hematopoietic cells as vehicles for targeting sites of inflammation with therapeutically active agents.

Key Words: inflammation • secretory lysosome • endosome pathway




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