Negative transcriptional regulation of the interferon-γ promoter by glucocorticoids and dominant negative mutants of c-Jun

Academic Article

Abstract

  • Interferon-γ (IFN-γ) is an immunoregulatory cytokine expressed in large granular lymphocytes and T cells. However, the molecular mechanisms underlying IFN-γ gene transcription have not been fully defined. Here, we analyze the mechanisms responsible for the inhibition of IFN-γ promoter activity by the glucocorticoid hormone dexamethasone. Cotransfection assays performed in Jurkat T cells demonstrated that the activity of the initial 108 base pairs of the IFN-γ promoter was downregulated in the presence of dexamethasone. Furthermore, utilizing electrophoretic mobility shift analysis, we identified activator protein 1 AP-1-cAMP response element binding protein-activating transcription factor (CREB-ATF) binding elements situated in positions of the IFN-γ promoter previously identified as essential for promoter activity. Moreover, dominant negative mutants of the c-Jun proto-oncogene were able to mimic the same down-regulatory effect exerted by dexamethasone, and mutations that abolished the binding of the AP- 1·CREB-ATF factors were able to block the glucocorticoid effect. These results suggest a model involving the inhibition of IFN-γ AP-1·CREB-ATF DNA binding complexes as one of the mechanisms involved in the negative regulatory action of glucocorticoids on IFN-γ gene expression and support the relevance of AP-1·CREB-ATF binding factors during the transcriptional activation of the IFN-γ promoter in T cells.
  • Digital Object Identifier (doi)

    Author List

  • Cippitelli M; Sica A; Viggiano V; Ye J; Ghosh P; Birrer MJ; Young HA
  • Start Page

  • 12548
  • End Page

  • 12556
  • Volume

  • 270
  • Issue

  • 21