title: Inhibition of IFN-gamma signaling by glucocorticoids.
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.
authors.affiliation: Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Hu
authors.forename: Wai-Ping
authors.initials: WP
authors.lastname: Li
authors.forename: Charis
authors.initials: C
authors.lastname: Meng
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects* / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000097:blood; D008894:Milk Proteins; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D007166:Immunosuppressive Agents; D050856:Interferon Regulatory Factor-1; D018950:Lipopolysaccharide Receptors; D008894:Milk Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D003907:Dexamethasone; D007371:Interferon-gamma