Document Detail


The combination of IκB kinase β inhibitor and everolimus modulates expression of interleukin-10 in human T-cell lymphotropic virus type-1-infected T cells.
MedLine Citation:
PMID:  23278479     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Adult T-cell leukaemia-lymphoma (ATLL) is an aggressive malignancy of CD4(+)  CD25(+) T lymphocytes, characterized by a severely compromised immunosystem, in which the human T-cell lymphotropic virus type 1 (HTLV-1) has been recognized as the aetiological agent. This study found that an IκB kinase β (IKKβ) inhibitor Bay11-7082 inactivated mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 and transcription factor nuclear factor-κB in HTLV-1-infected T cells; this was significantly enhanced in the presence of the mTOR inhibitor everolimus. In addition, Bay11-7082 decreased production of the immunosuppressive cytokine interleukin-10 (IL-10), which was further down-regulated when Bay11-7082 was combined with evelolimus in HTLV-1-infected T and ATLL cells isolated from patients. Interleukin-10 is known to inhibit maturation and the antigen-presenting function of dendritic cells (DCs). The culture media of HTLV-1-infected MT-1 cells, which contained a large amout of IL-10, hampered tumour necrosis factor-α-induced maturation of DCs isolated from healthy volunteers. Culture supernatant of MT-1 cells treated with a combination of Bay11-7082 and everolimus augmented maturation of DCs in association with a decrease in production of IL-10 and enhanced the allostimulatory function of DCs. Similarly, when DCs isolated from patients with ATLL were treated with the combination of Bay11-7082 and everolimus, they were fully matured and their capability to stimulate proliferation of lymphocytes was augmented. Taken together, the combination of Bay11-7082 and everolimus might exhibit immunostimulatory properties in HTLV-1-infected T and ATLL cells isolated from patients, and this combination may be potentially therapeutic to regain the compromised immunosystem in ATLL patients.
Authors:
Chie Nishioka; Takayuki Ikezoe; Jing Yang; Keiko Udaka; Akihito Yokoyama
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Immunology     Volume:  138     ISSN:  1365-2567     ISO Abbreviation:  Immunology     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-05     Completed Date:  2013-03-28     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  0374672     Medline TA:  Immunology     Country:  England    
Other Details:
Languages:  eng     Pagination:  216-27     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. Immunology © 2012 Blackwell Publishing Ltd.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Cell Line
Dendritic Cells / cytology,  drug effects
Gene Expression Regulation / drug effects*
HTLV-I Infections / genetics,  immunology*
Humans
I-kappa B Kinase / antagonists & inhibitors*,  metabolism
Interleukin-10 / genetics*,  metabolism
Lymphocyte Culture Test, Mixed
Monocytes / cytology,  drug effects
Nitriles / pharmacology
STAT3 Transcription Factor / metabolism
Signal Transduction / drug effects
Sirolimus / analogs & derivatives*,  pharmacology
Sulfones / pharmacology
T-Lymphocytes / immunology*,  metabolism*,  virology
TOR Serine-Threonine Kinases / metabolism
Transforming Growth Factor beta / genetics,  metabolism
Chemical
Reg. No./Substance:
0/3-(4-methylphenylsulfonyl)-2-propenenitrile; 0/Antineoplastic Agents; 0/Nitriles; 0/STAT3 Transcription Factor; 0/Sulfones; 0/Transforming Growth Factor beta; 130068-27-8/Interleukin-10; 159351-69-6/everolimus; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.10/I-kappa B Kinase; W36ZG6FT64/Sirolimus
Comments/Corrections

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