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BD 750, a benzothiazole derivative, inhibits T cell proliferation by affecting the JAK 3/ STAT 5 signalling pathway
Author(s) -
Liu Y,
Yang T,
Li H,
Li MH,
Liu J,
Wang YT,
Yang SX,
Zheng J,
Luo XY,
Lai Y,
Yang P,
Li LM,
Zou Q
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02172.x
Subject(s) - t cell , cell growth , flow cytometry , microbiology and biotechnology , chemistry , cytokine , cytotoxic t cell , viability assay , cell cycle , cell , in vitro , biology , immunology , biochemistry , immune system
Background and Purpose A series of benzothiazole derivatives were screened for immunosuppressive activity; of these compounds BD 750 was found to be the most effective immunosuppressant. The purpose of the current study was to determine the immunosuppressive activity of BD 750 on T cell proliferation and its potential mode of action. Experimental Approach T cell proliferation, CD 25 and CD 69 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 W estern blot analysis. The effects of BD 750 were evaluated in vivo in a mouse model of delayed‐type hypersensitivity. Key Results BD 750 significantly inhibited mouse and human T cell proliferation, stimulated either by anti‐ CD 3/anti‐ CD 28 monoclonal antibodies or by an alloantigen, in a dose‐dependent manner in vitro . No obvious cytotoxic effects of BD 750 were observed in our experimental conditions. Furthermore, BD 750 did not inhibit CD 25 and CD 69 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, BD 750 inhibited cell proliferation and STAT 5 phosphorylation, but not A kt or p70S6 K phosphorylation. BD 750 also reduced the T cell‐mediated delayed‐type hypersensitivity response in mice in a dose‐dependent manner. Conclusion and Implications These data indicate that BD 750 inhibits IL ‐2‐induced JAK 3/ STAT 5‐dependent T cell proliferation. BD 750 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.