Abstract
Although interferon beta (IFNbeta) decreases relapse rate and disease activity in multiple sclerosis (MS), the mechanisms involved have not been elucidated. The present study is the first report on the apoptotic effect of IFNbeta in mature, but not immature, myeloid dendritic cells (DCs). Both exogenous IFNbeta added to DCs matured through exposure to proinflammatory cytokines and endogenous IFNbeta secreted after lipopolysaccharide stimulation induced DC cell death. Apoptosis of mature DCs required both NF-kappaB and STAT-1 activation, and was mediated through the induction of caspase-11 expression and activation of caspase-3. In vivo, we observed increased caspase-11 expression and a significant decrease in the number of splenic DCs after lipopolysaccharide administration in wt but not in STAT-1-deficient mice. Since mature DCs are major contributors to the inflammatory response and essential partners in the induction of adaptive immunity, IFNbeta-dependent elimination of activated DCs could play an essential role in re-establishing homeostasis, and might represent a new molecular mechanism for the therapeutic effect of IFNbeta in MS.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis*
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Caspase 3 / biosynthesis*
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Caspase 3 / genetics
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Caspases / biosynthesis*
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Caspases / genetics
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Caspases, Initiator
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Dendritic Cells / enzymology*
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics
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Homeostasis / drug effects
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Homeostasis / genetics
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Humans
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Inflammation / drug therapy
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Inflammation / enzymology
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Inflammation / genetics
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Interferon-beta / genetics
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Interferon-beta / metabolism*
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Interferon-beta / pharmacology
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Lipopolysaccharides / pharmacology
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Multiple Sclerosis / drug therapy
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Multiple Sclerosis / enzymology*
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Multiple Sclerosis / genetics
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Myeloid Cells / enzymology
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NF-kappa B / genetics
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NF-kappa B / metabolism
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / metabolism
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Spleen / enzymology
Substances
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Lipopolysaccharides
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NF-kappa B
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STAT1 Transcription Factor
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Stat1 protein, mouse
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Interferon-beta
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Casp3 protein, mouse
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Casp4 protein, mouse
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Caspase 3
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Caspases
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Caspases, Initiator