IFN-beta inhibits dendritic cell migration through STAT-1-mediated transcriptional suppression of CCR7 and matrix metalloproteinase 9.
IFN-beta is an approved therapeutic option for the treatment of multiple sclerosis. The molecular mechanisms underlying the effects of IFN-beta in multiple sclerosis are not fully understood. Migration of dendritic cells (DCs) from the inflammatory site to draining lymph nodes for Ag presentation and activation of naive T cells and to the CNS for reactivation of encephalitogenic T cells requires CCR7 and matrix metalloproteinase (MMP)-9 expression. This article reports for the first time that IFN-beta inhibits CCR7 expression and MMP-9 production in mature DCs and reduces their migratory capacity. The effect of IFN-beta is mediated through STAT-1. In vivo treatment with IFN-beta results in lower numbers of DCs migrating to the draining lymph node following exposure to FITC and in reduced expression of CCR7 and MMP-9 in splenic CD11c(+) DCs following LPS administration. IFN-beta and IFN-gamma share the same properties in terms of their effects on CCR7, MMP-9, and DC migration, but they have opposite effects on IL-12 production. In addition, IFN-beta-treated DCs have a significantly reduced capacity for activating CD4(+) T cells and generating IFN-gamma-producing Th1 cells. The suppression of mature DC migration through negative regulation of CCR7 and MMP-9 expression represents a novel mechanism for the therapeutic effect of IFN-beta.
Yen
Jui-Hung
JH
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Kong
Weimin
W
Ganea
Doina
D
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D007155:Immunologic Factors / Q000276:immunology / Q000494:pharmacology*; D016899:Interferon-beta / Q000276:immunology / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054400:Receptors, CCR7 / Q000187:drug effects / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects
C515371:Ccr7 protein, mouse; D007155:Immunologic Factors; D054400:Receptors, CCR7; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D018664:Interleukin-12; D016899:Interferon-beta; D020780:Matrix Metalloproteinase 9