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

Content Provider	Journal of Biological Chemistry (JBC)
Author	Cristillo, Anthony D. Bierer, Barbara E.
Abstract	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.
Related Links	http://www.jbc.org/content/277/6/4465.abstract
Ending Page	4476
Starting Page	4465
Page Count	12
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	6
Volume Number	277
DOI	10.1074/jbc.M108598200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2002-02-08
Access Restriction	Open
Subject Keyword	T cell receptor (TcR) Nuclear factor of activated T cells (NFAT) Interleukin (IL) Cyclosporin A (CsA) Tacrolimus (FK506) Cyclophilin (CyP) FK506-binding protein (FKBP) Tumor necrosis factor α (TNFα) Peripheral blood T lymphocytes (PBL) Phosphate-buffered saline (PBS) Monoclonal antibody (mAb) Phorbol 12-myristate 13-acetate (PMA) Reverse transcriptase-PCR (RT-PCR) Signal transducers and activators of transcription (STAT) Actinomycin D (ActD) Expressed sequence tag (EST) MECHANISMS OF SIGNAL TRANSDUCTION
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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