Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation.
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.
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
S
S
Matsuda
F
F
Shibasaki
K
K
Takehana
H
H
Mori
E
E
Nishida
S
S
Koyasu
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019703:Calcineurin / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D020104:Immunophilins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000494:pharmacology; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D021381:Protein Transport; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
C113585:A238L protein, African swine fever virus; D048868:Adaptor Proteins, Signal Transducing; C491861:CABIN1 protein, human; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D008024:Ligands; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D014764:Viral Proteins; D016572:Cyclosporine; D008156:Luciferases; D005982:Glutathione Transferase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019703:Calcineurin; D020104:Immunophilins; D016559:Tacrolimus