Negative transcriptional regulation of human interleukin 2 (IL-2) gene by glucocorticoids through interference with nuclear transcription factors AP-1 and NF-AT

Fotini Paliogianni, Anastasios Raptis, Seema S. Ahuja, Sonia M. Najjar, Dimitrios T. Boumpas

Research output: Contribution to journalArticlepeer-review

174 Scopus citations

Abstract

IL-2 gene transcription is affected by several nuclear proteins. We asked whether dexamethasone (Dex) and cyclosporin A (CsA) inhibit IL-2 gene transcription by interfering with the activity of nuclear proteins that bind to the IL-2 promoter. Nuclear extracts from primary human T lymphocytes were analyzed by electrophoretic DNA mobility shift assays. Both Dex and CsA inhibited the binding of transcription factors AP-1 and NF-AT, but not of NF-kB and OCT-1/OAF, to their corresponding sites on the IL-2 gene promoter. To correlate changes in nuclear factor binding in vitro with transcriptional activity in vivo and define the structural requirements for IL-2 promoter repression, we used transient DNA transfections. Jurkat cells were transfected with plasmids containing either the intact IL-2 promoter or its AP-1, NF-AT, and NF-kB motifs. Dex inhibited the IL-2 promoter and the AP-I, but not the NF-AT and NF-kB plasmids. In contrast, CsA inhibited the IL-2 promoter and the NF-AT, but not the AP-1 and NF-kB plasmids. These results suggest that in human T lymphocytes both Dex and CsA inhibited IL-2 gene transcription through interference with transcription factors AP-I and NF-AT. We propose that, while maximum inhibition may involve interaction with both transcription factors, AP-1 is the primary target of Dex.

Original languageEnglish (US)
Pages (from-to)1481-1489
Number of pages9
JournalJournal of Clinical Investigation
Volume91
Issue number4
DOIs
StatePublished - Apr 1993

Keywords

  • Gene transcription
  • Glucocorticoids
  • Interleukin 2
  • Nuclear factor AP-1
  • Nuclear factor AT

ASJC Scopus subject areas

  • Medicine(all)

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