Identification of Novel Targets of Immunosuppressive Agents by cDNA-based Microarray Analysis

The immunosuppressive agents cyclosporin A (CsA) and tacrolimus (FK506) bind to unrelated intracellular immunophilin receptors, cyclophilin (CyP) and FK506-binding protein (FKBP), respectively. The complexes of CsA·CyP and of FK506·FKBP both bind to and inhibit the activity of the calcium/calmodulin...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-02, Vol.277 (6), p.4465-4476
Main Authors: Cristillo, Anthony D., Bierer, Barbara E.
Format: Article
Language:English
Subjects:
Base Sequence
calcineurin
cDNA microarrays
cyclophilin
cyclosporin A
Cyclosporine - pharmacology
DNA microarrays
DNA Primers
DNA, Complementary
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Enzyme-Linked Immunosorbent Assay
FK506
FKBP protein
Gene Expression Regulation - drug effects
Humans
Immunosuppressive Agents - pharmacology
Interleukin-16 - genetics
Interleukin-16 - metabolism
Milk Proteins
Multigene Family
Oligonucleotide Array Sequence Analysis
RNA, Messenger - genetics
STAT5 Transcription Factor
Stat5a protein
T-Lymphocytes - drug effects
T-Lymphocytes - metabolism
tacrolimus
Tacrolimus - pharmacology
Trans-Activators - genetics
Trans-Activators - metabolism
Tumor Suppressor Proteins
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Summary:The immunosuppressive agents cyclosporin A (CsA) and tacrolimus (FK506) bind to unrelated intracellular immunophilin receptors, cyclophilin (CyP) and FK506-binding protein (FKBP), respectively. The complexes of CsA·CyP and of FK506·FKBP both bind to and inhibit the activity of the calcium/calmodulin-dependent serine/threonine phosphatase calcineurin. We used cDNA microarray analysis to characterize early human peripheral blood T cell transcriptional responses following antigen receptor stimulation in the absence or presence of CsA or FK506, hoping to identify novel targets dependent upon calcineurin or immunophilins or, perhaps, specific targets of either CyP or FKBP inhibitable by one drug alone. The array data failed to identify genes uniquely sensitive to only one drug, suggesting that transcriptionally regulated, immunophilin-dependent but calcineurin-independent targets fell below the limits of detection in this system. In contrast, transcript profiling identified and mRNA and protein analysis confirmed novel as well as known genes reproducibly induced or inhibited by both immunosuppressive agents. In this context, we show that transcriptional activation of Stat5a and repression of the cytokine interleukin-16 are regulated by T cell receptor engagement and dependent upon drug-immunophilin complexes and, presumably, calcineurin activity.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M108598200