| Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis. | |
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MedLine Citation:
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PMID: 20956804 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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Dendritic cells (DCs) play a pivotal role in the pathogenesis of inflammatory disorders, so suppressing the activity of DCs is instrumental in treating such diseases. In the present study, we show that a proteasome inhibitor, bortezomib, suppresses the survival and immunostimulatory function of human plasmacytoid DCs (pDCs) by targeting 2 critical points, intracellular trafficking of nucleic acid-sensingToll-like receptors (TLRs) and endoplasmic reticulum (ER) homeostasis. Among the immune cells in blood, pDCs were the most susceptible to the killing effect of bortezomib. This correlates with a decrease in the spliced form of a transcription factor XBP1, which rescues cells from apoptosis by maintaining ER homeostasis. Bortezomib suppressed the production of interferon-α and interleukin-6 by pDCs activated with a TLR9-stimulating CpG DNA and a TLR7-stimulating influenza virus, which appears to be partially independent of apoptosis. Bortezomib inhibited translocation of TLR9 from the ER to endolysosomes but not of an ER membrane protein, Unc93B1, that delivers TLR9 to endolysosomes. Thus, bortezomib suppresses the activity of pDCs by inhibiting intracellular trafficking of TLRs through disrupting the coordinated translocation of TLRs and Unc93B1 and by disturbing ER homeostasis. This study suggests that proteasome inhibitors may alleviate inflammatory disorders such as lupus and psoriasis that involve pDCs. |
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Authors:
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Makiko Hirai; Norimitsu Kadowaki; Toshio Kitawaki; Haruyuki Fujita; Akifumi Takaori-Kondo; Ryutaro Fukui; Kensuke Miyake; Takahiro Maeda; Shimeru Kamihira; Yoshiki Miyachi; Takashi Uchiyama |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-18 |
Journal Detail:
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Title: Blood Volume: 117 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-14 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 500-9 Citation Subset: AIM; IM |
Affiliation:
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Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. |
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| Comments/Corrections | |
Comment In:
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Blood. 2011 Jan 13;117(2):376-7
[PMID:
21233320
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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