2011年1月
Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis
BLOOD
- 巻
- 117
- 号
- 2
- 開始ページ
- 500
- 終了ページ
- 509
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1182/blood-2010-05-284737
- 出版者・発行元
- AMER SOC HEMATOLOGY
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-sensing Toll-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-alpha 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. (Blood. 2011; 117(2):500-509)
- リンク情報
-
- DOI
- https://doi.org/10.1182/blood-2010-05-284737
- J-GLOBAL
- https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201202286331476178
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/20956804
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000286178700020&DestApp=WOS_CPL
- ID情報
-
- DOI : 10.1182/blood-2010-05-284737
- ISSN : 0006-4971
- J-Global ID : 201202286331476178
- PubMed ID : 20956804
- Web of Science ID : WOS:000286178700020