Document Detail


BD750, a benzothiazole derivative, inhibits T cell proliferation by affecting the JAK3/STAT5 signalling pathway.
MedLine Citation:
PMID:  22906008     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: A series of benzothiazole derivatives were screened for immunosuppressive activity; of these compounds BD750 was found to be the most effective immunosuppressant. The purpose of the current study was to determine the immunosuppressive activity of BD750 on T cell proliferation and its potential mode of action.
EXPERIMENTAL APPROACH: T cell proliferation, CD25 and CD69 expression and cell cycle distribution were measured in vitro by flow cytometry. Cell viability was determined by CCK-8 assay. Cytokine levels were measured by elisa. The activation of signal-regulated molecules was assessed by Western blot analysis. The effects of BD750 were evaluated in vivo in a mouse model of delayed-type hypersensitivity.
KEY RESULTS: BD750 significantly inhibited mouse and human T cell proliferation, stimulated either by anti-CD3/anti-CD28 monoclonal antibodies or by an alloantigen, in a dose-dependent manner in vitro. No obvious cytotoxic effects of BD750 were observed in our experimental conditions. Furthermore, BD750 did not inhibit CD25 and CD69 expression or IL-2 and IL-4 secretion, but induced cell cycle arrest at the G(0) /G(1) phase in activated T cells. In IL-2-stimulated CTLL-2 cells and primary activated T cells, BD750 inhibited cell proliferation and STAT5 phosphorylation, but not Akt or p70S6K phosphorylation. BD750 also reduced the T cell-mediated delayed-type hypersensitivity response in mice in a dose-dependent manner.
CONCLUSION AND IMPLICATIONS: These data indicate that BD750 inhibits IL-2-induced JAK3/STAT5-dependent T cell proliferation. BD750 has the potential to be used as a lead compound for the design and development of new immunosuppressants for preventing graft rejection and treating autoimmune diseases.
Authors:
Y Liu; T Yang; H Li; M-H Li; J Liu; Y-T Wang; S-X Yang; J Zheng; X-Y Luo; Y Lai; P Yang; L-M Li; Q Zou
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  168     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-17     Completed Date:  2013-07-02     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  632-43     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Descriptor/Qualifier:
Allergens
Animals
Benzothiazoles / pharmacology*,  therapeutic use
Cell Cycle / drug effects
Cell Proliferation / drug effects
Dinitrofluorobenzene
Female
Humans
Hypersensitivity, Delayed / chemically induced,  drug therapy,  pathology
Immunosuppressive Agents / pharmacology*,  therapeutic use
Indazoles / pharmacology*,  therapeutic use
Interleukin-2 / pharmacology
Janus Kinase 3 / metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
STAT5 Transcription Factor / metabolism
Signal Transduction
T-Lymphocytes / drug effects*,  metabolism
Chemical
Reg. No./Substance:
0/2-(2-benzothiazoleyl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 0/Allergens; 0/Benzothiazoles; 0/Immunosuppressive Agents; 0/Indazoles; 0/Interleukin-2; 0/STAT5 Transcription Factor; D241E059U6/Dinitrofluorobenzene; EC 2.7.10.2/Janus Kinase 3
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