Open Access

REVIEW

Hematopoietic secretory granules as vehicles for the local delivery of cytokines and soluble cytokine receptors at sites of inflammation

Markus Hansson¹, Ying Gao¹, Hanna Rosén¹, Hans Tapper², Inge Olsson¹

1 Department of Hematology, C14, BMC, SE-221 84 Lund, Sweden
2 Department of Cell and Molecular Biology, B14, BMC, SE-22184 Lund, Sweden

* Corresponding Author: Markus Hansson,

European Cytokine Network 2004, 15(3), 167-176.

Accepted 17 June 2004;

Abstract

Cytokines play an important role in the regulation of homeostasis and inflammation. A de-regulated cytokine function can subsequently promote chronic inflammation. This is supported by clinical evidence showing the beneficial effect of inhibiting TNF-α through injection of antibodies and soluble receptor in disorders such as rheumatoid arthritis and Crohn’s disease. Systemic anti-TNF-α therapy however is associated with infectious complications. We therefore suggest a concept for the local deposition of therapeutically active agents into areas of inflammation or malignancy, based on the use of hematopoietic storage and secretory granules as delivery vehicles. Hematopoietic cells are induced to express the therapeutically active protein and to store it in the secretory lysosomes. The cells migrate into a tumour or site of inflammation, where the cells become activated and release the contents of their secretory lysosomes resulting in the local delivery of the therapeutically active protein. In support of this concept, gene transfer and granule loading can be achieved using the soluble TNF-a receptor (sTNFR1) after cDNA expression in hematopoietic cell lines. Endoplasmic reticulum (ER)-export can be facilitated by the addition of a transmembrane domain, and constitutive secretion can be prevented by incorporating a cytosol-sorting signal resulting in secretory lysosome targeting. The sTNFR1 is released from the transmembrane domain by proteolytic cleavage and finally, regulated sTNFR1-secretion can be triggered by a calcium signal. In vivo investigations are currently determining the feasibility of local protein delivery at sites of inflammation.

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Keywords

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