Inhibition of IL-2-induced Jak-STAT signaling by glucocorticoids

Inhibition of IL-2-induced Jak-STAT signaling by glucocorticoids

^*Department of Medicine, Hospital for Special Surgery, ^†Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021

Edited by Anthony Cerami, The Kenneth S. Warren Laboratories, Tarrytown, NY, and approved June 14, 2000 (received for review March 7, 2000)

Abstract

Glucocorticoids (GCs) are potent anti-inflammatory agents that block cytokine production. We investigated whether GCs also block cytokine signaling via the Janus kinase (Jak)-signal transducer and activator of transcription (STAT) pathway. Dexamethasone inhibited IL-2-induced DNA binding, tyrosine phosphorylation, and nuclear translocation of Stat5 in primary T cells. Inhibition of Stat5 correlated with inhibition of expression of IL-2-inducible genes and T cell proliferation. The mechanism of inhibition involved suppression of IL-2 receptor and Jak3 expression. Signaling by IL-4, IL-7, and IL-15, which use IL-2 receptor components, also was inhibited, indicating a block in T cell responses similar to that seen in immunodeficient patients lacking the IL-2 receptor gamma chain or Jak3. IL-2 signaling also was blocked in patients after treatment with GCs, suggesting that inhibition of cytokine signaling contributes to the clinical efficacy of these agents. These results identify inhibition of Jak-STAT signaling by IL-2 and related cytokines as a novel mechanism of GC action and suggest that inhibition of both cytokine production and signaling contribute to their therapeutic potency.

Footnotes

↵ ‡ To whom reprint requests should be addressed at: Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail: IvashkivL{at}HSS.edu.
This paper was submitted directly (Track II) to the PNAS office.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.160099797.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.160099797
Abbreviations:

GC,

glucocorticoid;

STAT,

signal transducer and activator of transcription;

Jak,

Janus kinase;

EMSA,

electrophoretic mobility shift assay;

AP-1,

activation protein-1;

γc,

common γ chain;

dex,

dexamethasone;

IL-2R,

IL-2 receptor;

IB,

immunoblotting