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The Journal of Immunology, 2001, 166: 5665-5674.
Copyright © 2001 by The American Association of Immunologists

Protein Kinase C-{theta} Participates in the Activation of Cyclic AMP-Responsive Element-Binding Protein and Its Subsequent Binding to the -180 Site of the IL-2 Promoter in Normal Human T Lymphocytes1

Elena E. Solomou, Yuang-Taung Juang and George C. Tsokos2

Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910; and Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD 20814

IL-2 gene expression is regulated by the cooperative binding of discrete transcription factors to the IL-2 promoter/enhancer and is predominantly controlled at the transcriptional level. In this study, we show that in normal T cells, the -180 site (-164/-189) of the IL-2 promoter/enhancer is a p-cAMP-responsive element-binding protein (p-CREB) binding site. Following activation of the T cells through various membrane-initiated and membrane-independent pathways, protein kinase C (PKC)-{theta} phosphorylates CREB, which subsequently binds to the -180 site and associates with the transcriptional coactivator p300. Rottlerin, a specific PKC-{theta} inhibitor, diminished p-CREB protein levels when normal T cells were treated with it. Rottlerin also prevented the formation of p-CREB/p300 complexes and the DNA-CREB protein binding. Cotransfection of fresh normal T cells with luciferase reporter construct driven by two tandem -180 sites and a PKC-{theta} construct caused a significant increase in the transcription of the reporter gene, indicating that this site is functional and regulated by PKC-{theta}. Cotransfection of T cells with a luciferase construct driven by the -575/+57 region of the IL-2 promoter/enhancer and a PKC-{theta} construct caused a similar increase in the reporter gene transcription, which was significantly limited when two bases within the -180 site were mutated. These findings show that CREB plays a major role in the transcriptional regulation of IL-2 and that a major pathway for the activation of CREB and its subsequent binding to the IL-2 promoter/enhancer in normal T cells is mediated by PKC-{theta}.




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