Molecular and functional evidence for in vitro cytokine enhancement of human and murine target cell sensitivity to glucocorticoids. TNF-alpha priming increases glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis

M Costas, T Trapp, M P Pereda, J Sauer, R Rupprecht, V E Nahmod, J M Reul, F Holsboer, E Arzt

Research output: Contribution to journalArticle (Academic Journal)

62 Citations (Scopus)

Abstract

Cytokine-induced glucocorticoid secretion and glucocorticoid inhibition of cytokine synthesis and pleiotropic actions act as important safeguards in preventing cytokine overreaction. We found that TNF-alpha increased glucocorticoid-induced transcriptional activity of the glucocorticoid receptor (GR) via the glucocorticoid response elements (GRE) in L-929 mouse fibroblasts transfected with a glucocorticoid-inducible reporter plasmid. In addition, TNF-alpha also enhanced GR number. The TNF-alpha effect on transcriptional activity was absent in other cell lines that express TNF-alpha receptors but not GRs, and became manifest when a GR expression vector was cotransfected, indicating that TNF-alpha, independent of any effect it may have on GR number, has a stimulatory effect on the glucocorticoid-induced transcriptional activity of the GR. Moreover, TNF-alpha increased GR binding to GRE. As a functional biological correlate of this mechanism, priming of L-929 cells with a low (noncytotoxic) dose of TNF-alpha significantly increased the sensitivity to glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis. TNF-alpha and IL-1 beta had the same stimulatory action on glucocorticoid-induced transcriptional activity of the GR via the GRE, in different types of cytokine/glucocorticoid target cells (glioma, pituitary, epithelioid). The phenomenon may therefore reflect a general molecular mechanism whereby cytokines modulate the transcriptional activity of the GR, thus potentiating the counterregulation by glucocorticoids at the level of their target cells.

Original languageEnglish
Pages (from-to)1409-16
Number of pages8
JournalJournal of Clinical Investigation
Volume98
Issue number6
DOIs
Publication statusPublished - 15 Sep 1996

Keywords

  • Animals
  • Apoptosis
  • Cells, Cultured
  • Cytotoxicity, Immunologic
  • Dexamethasone
  • Genes, Reporter
  • Glucocorticoids
  • HeLa Cells
  • Humans
  • Interleukin-1
  • Mice
  • Plasmids
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Transcription, Genetic
  • Transfection
  • Tumor Necrosis Factor-alpha

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