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Two distinct action mechanisms of immunophilin–ligand complexes for the blockade of T‐cell activation
Author(s) -
Matsuda Satoshi,
Shibasaki Futoshi,
Takehana Kenji,
Mori Hiroaki,
Nishida Eisuke,
Koyasu Shigeo
Publication year - 2000
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1093/embo-reports/kvd090
Subject(s) - nfat , calcineurin , jurkat cells , fkbp , kinase , microbiology and biotechnology , p38 mitogen activated protein kinases , biology , signal transduction , mapk/erk pathway , mitogen activated protein kinase , t cell , chemistry , transplantation , immunology , medicine , immune system , surgery
The immunosuppressive effects of cyclosporin A (CsA) and FK506 are mediated through binding to immunophilins. Here we show that FK506–FKBP complex suppresses the activation of JNK and p38 pathways at a level upstream of mitogen‐activated protein kinase (MAPK) kinase kinase (MAPKK‐K) besides the calcineurin–NFAT pathway. A238L, a viral gene product that binds to immunophilin, also blocks activation of both pathways. In contrast, direct inhibitors of calcineurin, Cabin 1 and FR901725, suppress the activation of NFAT but not the JNK or p38 pathway. We further demonstrate that co‐expression of a constitutively active NFAT and a constitutively active MEKK1 renders the interleukin‐2 promoter in Jurkat T lymphocytes resistant to CsA and FK506, whereas Jurkat cells expressing a constitutively active NFAT alone are still sensitive to CsA or FK506. Therefore, CsA and FK506 exert their immunosuppressive effects through targeting both the calcineurin‐dependent NFAT pathway and calcineurin‐independent activation pathway for JNK and p38.