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Papers In Press, published online ahead of print November 1, 2001
Laboratory of Lymphocyte Biology, National Institutes of Health, Bethesda, Maryland 20892
Corresponding Author: BiererB{at}nhlbi.nih.gov
The immunosuppressive agents cyclosporine (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 IL-16 are regulated by TcR engagement and dependent upon immunophilin and, presumably, calcineurin activity.
J. Biol. Chem, 10.1074/jbc.M108598200
Submitted on September 6, 2001
Revised on October 29, 2001
Accepted on November 1, 2001
Identification of novel targets of immunosuppressive agents by cDNA-based microarray analysis
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