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Rapamycin antagonizes cyclosporin A- and tacrolimus (FK506)-mediated augmentation of linker for activation of T cell expression in T cells. Int Immunol 2003 Nov;15(11):1369-78

Date

10/21/2003

Pubmed ID

14565935

DOI

10.1093/intimm/dxg138

Abstract

The discovery of new immunosuppressive drugs such as rapamycin, cyclosporin A (CsA) and tacrolimus (FK506) has been very useful for preventing graft rejection and autoimmune disease. However, these drugs are not specific, and are associated with side-effects and toxicities. Therefore, understanding the molecular mechanisms of these drugs is important for designing specific immunosuppressants. Here, we show that in contrast to CsA and FK506, rapamycin blocks activation-induced expression of the linker for activation of T cells (LAT), a signaling molecule critical for initiating TCR signaling. Thus, whereas CsA and FK506 strongly enhanced TCR- and phorbol myristate acetate-induced LAT expression in T cells, rapamycin effectively inhibited activation-induced LAT expression. Importantly, these opposite effects were mutually antagonistic, as rapamycin acted as a potent antagonist for both CsA and FK506. Because CsA, unlike FK506 and rapamycin, does not bind to the intracellular immunophilin FK-binding protein (FKBP), the antagonism between these drugs is not simply due to competition for intracellular FKBP. Accordingly, RNA and protein stability analyses suggest inhibition by rapamycin at the translational level. Given the important role of LAT in initiating T cell activation, our data suggests that the effects of rapamycin, CsA and FK506 on T cell activation involve regulating early T cell signaling. These findings refine our understanding of the manifold effects of these immunosuppressants, thus providing insight into the drastic physiological contrasts observed between these drugs.

Author List

Cho CS, Chang Z, Elkahwaji J, Scheunemann TL, Manthei ER, Colburn M, Knechtle SJ, Hamawy MM

Author

Tara L. Petersen MD, MSED Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Base Sequence
Carrier Proteins
Cell Line, Tumor
Cyclosporine
Humans
Immunosuppressive Agents
Lymphocyte Activation
Membrane Proteins
Molecular Sequence Data
Phosphoproteins
Protein Processing, Post-Translational
RNA, Messenger
Signal Transduction
Sirolimus
T-Lymphocytes
Tacrolimus
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a