Polyamine compound deoxyspergualin inhibits heat shock protein-induced activation of immature dendritic cells |
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Authors: | Atsushi Sugawara Toshihiko Torigoe Yasuaki Tamura Kenjiro Kamiguchi Kyuichi Nemoto Hiroshi Oguro Noriyuki Sato |
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Institution: | (1) Department of Pathology (Section 1), Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo 060-8556, Japan;(2) Department of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo, Japan;(3) Nippon Kayaku, Co. Ltd., Tokyo, Japan |
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Abstract: | Polyamine compound deoxyspergualin (DSG) is a potent immunosuppressive agent that has been applied clinically for protecting
graft rejection and treatment of Wegener's granulomatosis. Though DSG can bind to heat-shock proteins (HSPs) in cells, its
mechanism of immunosuppressive action remains unknown. It is widely accepted that extracellular HSPs are capable of stimulating
dendritic cells (DC) through cell surface receptors, leading to DC activation and cytokine release. In this study, we examined
if DSG analogs could inhibit HSP70-induced DC activation. Bone marrow derived immature mouse DCs and peripheral blood mononuclear
cell-derived immature human DCs were generated and incubated with Alexa 488-labeled Hsp70 in the presence of methoxyDSG (Gus-1)
that had comparable HSP70-binding affinity to DSG or DSG analog GUS-7, which had much more reduced binding affinity for HSP70.
The binding of HSP70 to immature DCs was analyzed by laser microscopy and flow cytometry. HSP70-induced DC activation was
assessed by TNF-α release by enzyme-linked immunosorbent assay. Binding of Hsp70 to the cell surface of immature DCs was inhibited
under the presence of Gus-1, but not under the presence of Gus-7. Immature DCs were activated and released TNF-α by the stimulation
with HSP70 for 12 hours; however, the HSP70-induced TNF-α release was suppressed under the presence of Gus-1, and partially
suppressed under the presence of Gus-7. Similar results were observed when immature human DCs were stimulated under the same
conditions. Immunosuppressive mechanism of DSG may be explained, at least in part, by the inhibition of extracellular HSP70-DC
interaction and HSP70-induced activation of immature DCs.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | HSP70 Deoxyspergualin Dendritic cells Immunosuppressant |
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