These authors equally contributed to this work.
BD750, a benzothiazole derivative, inhibits T cell proliferation by affecting the JAK3/STAT5 signalling pathway
Article first published online: 16 JAN 2013
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society
British Journal of Pharmacology
Volume 168, Issue 3, pages 632–643, February 2013
How to Cite
Liu, Y., Yang, T., Li, H., Li, M.-H., Liu, J., Wang, Y.-T., Yang, S.-X., Zheng, J., Luo, X.-Y., Lai, Y., Yang, P., Li, L.-M. and Zou, Q. (2013), BD750, a benzothiazole derivative, inhibits T cell proliferation by affecting the JAK3/STAT5 signalling pathway. British Journal of Pharmacology, 168: 632–643. doi: 10.1111/j.1476-5381.2012.02172.x
- Issue published online: 16 JAN 2013
- Article first published online: 16 JAN 2013
- Accepted manuscript online: 21 AUG 2012 04:40AM EST
- Manuscript Accepted: 10 AUG 2012
- Manuscript Revised: 21 JUL 2012
- Manuscript Received: 8 MAR 2012
- New Century Excellent Talents in University. Grant Number: NCET-09–0888
- National Natural Science Foundation of China. Grant Numbers: 21172024, 81072455, 81273530, 81202363
- Sichuan Youth Science and Technology Fund. Grant Number: 2010JQ0035
- Scientific Research Fund of Sichuan Provincial Education Department. Grant Numbers: 11ZA201, 11ZB169
- Research Fund of Chengdu Medical College. Grant Number: CYZ09-019
- benzothiazol derivate;
- T cell proliferation;
- JAK3/STAT5 signal pathway
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.
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.
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 G0/G1 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.