Myocyte Enhancer Factor 2 Mediates Calcium-dependent Transcription of the Interleukin-2 Gene in T Lymphocytes
A CALCIUM SIGNALING MODULE THAT IS DISTINCT FROM BUT COLLABORATES WITH THE NUCLEAR FACTOR OF ACTIVATED T CELLS (NFAT)*
- ‡Department of Pharmacology and Molecular Science and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and the §Division of Immunology and Hematopoiesis, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231
- ↵¶ To whom correspondence should be addressed: Dept. of Pharmacology and Molecular Science and Dept. of Neuroscience, Johns Hopkins University School of Medicine, Hunterian Bldg., Rm. 516, 725 North Wolfe St., Baltimore, MD 21205. Tel.: 410-955-4619; Fax: 410-955-4620; E-mail: joliu{at}jhu.edu.
Abstract
The second messenger calcium plays an essential role in the T cell receptor-mediated signal transduction pathways leading to transcription of the interleukin-2 gene. A key mechanism of calcium signaling has been shown to be mediated by calcineurin and NFAT. We report herein that the transcription factor myocyte enhancer factor (MEF)-2 is another calcium signal transducer involved in the regulation of the interleukin (IL)-2 promoter. A MEF2-binding site was identified in proximity to the TATA box of the IL-2 promoter. This site was shown to be bound by MEF2 in both resting and activated T cells. Overexpression of MEF2 enhanced, while overexpression of a dominant negative form of MEF2 or the MEF2-specific transcriptional corepressors Cabin1 and histone deacetylase 4 inhibited, the T cell receptor-dependent activation of an IL-2 reporter gene. Down-regulation of MEF2 by RNA interference in primary human T cells led to the inhibition of endogenous IL-2 transcription. These results suggest that MEF2 is required for the transcriptional activation of IL-2 and likely other cytokine genes in response to calcium signaling and may serve as a novel target for development of immunosuppressants.
- Received November 10, 2003.
- Revision received December 29, 2003.
- The American Society for Biochemistry and Molecular Biology, Inc.
