Glucocorticoids inhibit calcium- and calcineurin-dependent activation of the human IL-4 promoter

Rongbing Chen, Thomas F. Burke, John E. Cumberland, Mary Brummet, Lisa A. Beck, Vincenzo Casolaro, Steve N. Georas

Research output: Contribution to journalArticle

Abstract

The mechanism by which glucocorticoids (GC) inhibit IL-4 gene expression is currently unknown. In T lymphocytes, IL-4 gene expression is regulated at the level of transcription by increases in intracellular calcium concentration and by the calcium-activated phosphatase calcineurin. In this paper we report that dexamethasone (Dex) inhibits calcium ionophore-induced activation of the human IL-4 promoter in transiently transfected Jurkat T cells. Inhibition of the promoter by Dex is dependent on expression of the GC receptor (GR), because it does not occur in GR-deficient cells. Dex also represses activation of the promoter induced by cotransfecting cells with a constitutively active mutant of calcineurin. Using a series of deletion constructs, we show that the proximal 95 bp of the IL-4 promoter contain a Dex-sensitive regulatory element. This region contains the P1 sequence, a proximal binding site for NF-AT. A calcium-induced but Dex-inhibited nuclear complex containing NF-AT binds to the P1 element in EMSA. Using immunoprecipitation under nondenaturing conditions, we found that the GRα isoform coprecipitates with NF-ATc in nuclear extracts of calcium ionophore- and Dex-treated cells. Taken together, our results show that GC inhibit IL-4 gene expression by interfering with NF-AT-dependent transactivation of the proximal human IL-4 promoter.

Original languageEnglish (US)
Pages (from-to)825-832
Number of pages8
JournalJournal of Immunology
Volume164
Issue number2
DOIs
StatePublished - Jan 15 2000

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Chen, R., Burke, T. F., Cumberland, J. E., Brummet, M., Beck, L. A., Casolaro, V., & Georas, S. N. (2000). Glucocorticoids inhibit calcium- and calcineurin-dependent activation of the human IL-4 promoter. Journal of Immunology, 164(2), 825-832. https://doi.org/10.4049/jimmunol.164.2.825