title: Rapamycin antagonizes cyclosporin A- and tacrolimus (FK506)-mediated augmentation of linker for activation of T cell expression in T cells.
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.
authors.affiliation: Division of Transplantation, Department of Surgery, University of Wisconsin Medical School, Madison, WI 53792, USA.
authors.forename: Clifford S
authors.initials: CS
authors.lastname: Cho
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chang
authors.forename: Johny
authors.initials: J
authors.lastname: Elkahwaji
authors.forename: Tara L
authors.initials: TL
authors.lastname: Scheunemann
authors.forename: Eric R
authors.initials: ER
authors.lastname: Manthei
authors.forename: Matthew
authors.initials: M
authors.lastname: Colburn
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Knechtle
authors.forename: Majed M
authors.initials: MM
authors.lastname: Hamawy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016559:Tacrolimus / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; C110810:LAT protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus