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Signaling by Glucocorticoids1
* Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, and
Department of Medicine, Hospital for Special Surgery, New York, NY 10021
Recent reports suggest that a novel mechanism of glucocorticoid (GC) immunosuppressive action is inhibition of signaling by IL-2 and IL-12, cytokines that use the Janus kinase-STAT signaling pathway. We investigated whether GCs could also block activation of Janus kinase-STAT signaling by IFN-
, a potent proinflammatory cytokine. Addition of dexamethasone to PBMC cultures resulted in a dramatic inhibition of IFN- activation of STAT1. Several days of exposure to GCs were required for inhibition of IFN- signaling to become apparent, and the underlying mechanism was down-regulation of STAT1 expression. GCs suppressed the expression of STAT1 mRNA, but did not affect STAT1 protein stability. STAT1 expression and IFN- signaling were preferentially suppressed in macrophages. GCs did not act directly on macrophages, but worked indirectly by regulating macrophage-lymphocyte interactions that control STAT1 expression. GCs inhibited IFN--inducible gene expression, thus demonstrating the physiological significance of inhibition of signal transduction. Our results identify a novel level of regulation of IFN- signaling, whereby GCs control the amplitude of IFN- signaling by regulating STAT1 expression. These results suggest that inhibition of IFN- signaling contributes to the immunosuppressive action of GCs.
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