Two distinct action mechanisms of immunophilin–ligand complexes for the blockade of T‐cell activation

Two distinct action mechanisms of immunophilin–ligand complexes for the blockade of T‐cell... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png EMBO Reports Wiley

Two distinct action mechanisms of immunophilin–ligand complexes for the blockade of T‐cell activation

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Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
1469-221X
eISSN
1469-3178
DOI
10.1093/embo-reports/kvd090
pmid
11258483
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

EMBO ReportsWiley

Published: Nov 1, 2000

References

  • Cyclosporin A, FK‐506 and rapamycin: pharmacologic probes of lymphocyte signal transduction
    Sigal, N.H.; Dumont, F.J.
  • A radicicol‐related macrocyclic nonaketide compound, antibiotic LL‐Z1640‐2, inhibits the JNK/p38 pathways in signal‐specific manner
    Takehana, K.; Sato, S.‐i.; Kobayasi, T.; Maeda, T.
  • Construction of Epstein–Barr virus‐based expression vector containing mini‐OriP
    Tanaka, J.; Miwa, Y.; Miyoshi, K.; Ueno, A.; Inoue, H.

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