Abstract
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-gamma, a potent proinflammatory cytokine. Addition of dexamethasone to PBMC cultures resulted in a dramatic inhibition of IFN-gamma activation of STAT1. Several days of exposure to GCs were required for inhibition of IFN-gamma 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-gamma 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-gamma-inducible gene expression, thus demonstrating the physiological significance of inhibition of signal transduction. Our results identify a novel level of regulation of IFN-gamma signaling, whereby GCs control the amplitude of IFN-gamma signaling by regulating STAT1 expression. These results suggest that inhibition of IFN-gamma signaling contributes to the immunosuppressive action of GCs.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Anti-Inflammatory Agents / pharmacology
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Cells, Cultured
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Chemokine CXCL10
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Chemokines, CXC / antagonists & inhibitors
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Chemokines, CXC / biosynthesis
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Chemokines, CXC / genetics
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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Dexamethasone / pharmacology*
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Down-Regulation / drug effects*
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Down-Regulation / immunology*
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / immunology
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Humans
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Immunosuppressive Agents / pharmacology*
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Interferon Regulatory Factor-1
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Interferon-gamma / antagonists & inhibitors*
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Interferon-gamma / genetics
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Interferon-gamma / metabolism
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Interferon-gamma / physiology*
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / metabolism
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Lipopolysaccharide Receptors / biosynthesis
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Lipopolysaccharide Receptors / blood
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Milk Proteins*
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Monocytes / drug effects
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Monocytes / immunology
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Monocytes / metabolism
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / biosynthesis
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Phosphoproteins / genetics
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / biosynthesis
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STAT1 Transcription Factor
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STAT5 Transcription Factor
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Signal Transduction / drug effects*
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Signal Transduction / immunology*
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Time Factors
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
Substances
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Anti-Inflammatory Agents
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Chemokine CXCL10
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Chemokines, CXC
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DNA-Binding Proteins
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IRF1 protein, human
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Immunosuppressive Agents
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Interferon Regulatory Factor-1
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Lipopolysaccharide Receptors
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Milk Proteins
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Phosphoproteins
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RNA, Messenger
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT5 Transcription Factor
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Trans-Activators
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Dexamethasone
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Interferon-gamma