Novel mechanism for inhibition of human T cells by glucocorticoids. Glucocorticoids inhibit signal transduction through IL-2 receptor

J Immunol. 1993 Oct 15;151(8):4081-9.

Abstract

Interaction of IL-2 with its high affinity membrane receptor complex (IL-2R) present on activated T lymphocytes induces cell proliferation and mediates effector functions. Glucocorticoids inhibit IL-2 production by inhibiting TCR-mediated signal transduction. We asked whether they also inhibit the action of IL-2 by inhibiting signal transduction through IL-2R. Human peripheral blood T cells, stimulated with PMA for 48 h (PMA blasts), were incubated with IL-2 in the presence of incremental dosages of dexamethasone (Dex; 10(-5)-10(-9) M). Dex inhibited the IL-2-dependent proliferation of PMA blasts in a dose-dependent fashion (IC50, 5 x 10(-8) M). Cell surface expression of IL-2R alpha- and beta-chains as determined by immunofluorescence analysis was not affected by Dex. In addition, Scatchard plot analysis of 125I-labeled IL-2 showed that Dex did not affect the binding of IL-2, thus suggesting that inhibition is due to a postreceptor effect. Inhibition of T cell proliferation by Dex was associated with decreased IL-2-dependent tyrosine phosphorylation of several intracellular proteins and decreased phosphorylation of the retinoblastoma gene product Rb, a protein essential for controlling the progression of cells through the cell cycle. IL-2-dependent IL-2R alpha expression in PMA blasts and NF-kB induction in resting human T cells were also inhibited by Dex. These results demonstrate that glucocorticoids inhibit preactivated T cells by down-regulating signal transduction through IL-2R.

MeSH terms

  • Adult
  • Base Sequence
  • Cells, Cultured
  • Dexamethasone / pharmacology*
  • Humans
  • Interleukin-2 / pharmacology
  • Lymphocyte Activation / drug effects
  • Molecular Sequence Data
  • NF-kappa B / metabolism
  • Phosphorylation
  • Receptors, Interleukin-2 / physiology*
  • Signal Transduction / drug effects*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • Tyrosine / metabolism

Substances

  • Interleukin-2
  • NF-kappa B
  • Receptors, Interleukin-2
  • Tyrosine
  • Dexamethasone