LY294002 and rapamycin co-operate to inhibit T-cell proliferation
Article first published online: 29 JAN 2009
2005 British Pharmacological Society
British Journal of Pharmacology
Volume 144, Issue 6, pages 791–800, March 2005
How to Cite
Breslin, E. M., White, P. C., Shore, A. M., Clement, M. and Brennan, P. (2005), LY294002 and rapamycin co-operate to inhibit T-cell proliferation. British Journal of Pharmacology, 144: 791–800. doi: 10.1038/sj.bjp.0706061
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- (Received August 11, 2004, Revised September 30, 2004, Accepted October 15, 2004)
- cyclin D2;
- phosphatidylinositol-3 kinase (PI3K);
- T-cell proliferation;
- interleukin-2 (IL-2)
- 1T-cell proliferation is critical for mounting an effective adaptive immune response. It is regulated by signals through the T-cell receptor, through co-stimulation and through cytokines such as interleukin-2 (IL-2). Phosphatidylinositol 3-kinase (PI3K) lies downstream of each of these pathways and has been directly implicated in the regulation of lymphocyte proliferation.
- 2In this study, we have shown that PI3K regulates cyclin D2 and cyclin D3, the first cell cycle proteins induced in T-cell proliferation, transcriptionally and post-transcriptionally. In T-lymphoblasts, LY294002, a PI3K inhibitor, prevents the induction of both D-type cyclin mRNA and protein, while rapamycin inhibits the induction of protein. Rapamycin inhibits mammalian target of rapamycin (mTOR), which lies downstream of PI3K.
- 3Furthermore, our data show that the combination of LY294002 and rapamycin results in a co-operative inhibition of T-cell proliferation. This co-operation occurs in Kit225 cells stimulated with IL-2, and also in resting peripheral blood lymphocytes stimulated with antibodies to the T-cell receptor in the presence and absence of antibodies to CD28.
- 4These data indicate that PI3K regulates T-cell proliferation in response to diverse stimuli, and suggest that combinations of inhibitors, perhaps isoform-selective, may be useful as alternative immunosuppressive therapies.
British Journal of Pharmacology (2005) 144, 791–800. doi:10.1038/sj.bjp.0706061