PMID- 20956804
OWN - NLM
STAT- MEDLINE
DCOM- 20110223
LR  - 20210206
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 117
IP  - 2
DP  - 2011 Jan 13
TI  - Bortezomib suppresses function and survival of plasmacytoid dendritic cells by 
      targeting intracellular trafficking of Toll-like receptors and endoplasmic 
      reticulum homeostasis.
PG  - 500-9
LID - 10.1182/blood-2010-05-284737 [doi]
AB  - 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-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.
FAU - Hirai, Makiko
AU  - Hirai M
AD  - Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, 
      Japan.
FAU - Kadowaki, Norimitsu
AU  - Kadowaki N
FAU - Kitawaki, Toshio
AU  - Kitawaki T
FAU - Fujita, Haruyuki
AU  - Fujita H
FAU - Takaori-Kondo, Akifumi
AU  - Takaori-Kondo A
FAU - Fukui, Ryutaro
AU  - Fukui R
FAU - Miyake, Kensuke
AU  - Miyake K
FAU - Maeda, Takahiro
AU  - Maeda T
FAU - Kamihira, Shimeru
AU  - Kamihira S
FAU - Miyachi, Yoshiki
AU  - Miyachi Y
FAU - Uchiyama, Takashi
AU  - Uchiyama T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101018
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Boronic Acids)
RN  - 0 (Cytokines)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Pyrazines)
RN  - 0 (Regulatory Factor X Transcription Factors)
RN  - 0 (Toll-Like Receptors)
RN  - 0 (Transcription Factors)
RN  - 0 (X-Box Binding Protein 1)
RN  - 0 (XBP1 protein, human)
RN  - 69G8BD63PP (Bortezomib)
SB  - IM
CIN - Blood. 2011 Jan 13;117(2):376-7. PMID: 21233320
MH  - Apoptosis/drug effects
MH  - Boronic Acids/*pharmacology
MH  - Bortezomib
MH  - Cell Separation
MH  - Cytokines/biosynthesis
MH  - DNA-Binding Proteins/drug effects/metabolism
MH  - Dendritic Cells/*drug effects/immunology/metabolism
MH  - Endoplasmic Reticulum/*drug effects/metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Flow Cytometry
MH  - Homeostasis/*drug effects
MH  - Humans
MH  - Microscopy, Confocal
MH  - Protease Inhibitors/*pharmacology
MH  - Protein Transport/drug effects
MH  - Pyrazines/*pharmacology
MH  - Regulatory Factor X Transcription Factors
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Toll-Like Receptors/*drug effects/metabolism
MH  - Transcription Factors/drug effects/metabolism
MH  - X-Box Binding Protein 1
EDAT- 2010/10/20 06:00
MHDA- 2011/02/24 06:00
CRDT- 2010/10/20 06:00
PHST- 2010/10/20 06:00 [entrez]
PHST- 2010/10/20 06:00 [pubmed]
PHST- 2011/02/24 06:00 [medline]
AID - S0006-4971(20)59198-2 [pii]
AID - 10.1182/blood-2010-05-284737 [doi]
PST - ppublish
SO  - Blood. 2011 Jan 13;117(2):500-9. doi: 10.1182/blood-2010-05-284737. Epub 2010 Oct 
      18.