Abstract
Interleukin-10 is a predominantly anti-inflammatory cytokine that inhibits macrophage and dendritic cell function, but can acquire proinflammatory activity during immune responses. We investigated whether type I IFNs, which are elevated during infections and in autoimmune diseases, modulate the activity of IL-10. Priming of primary human macrophages with low concentrations of IFN-alpha diminished the ability of IL-10 to suppress TNF-alpha production. IFN-alpha conferred a proinflammatory gain of function on IL-10, leading to IL-10 activation of expression of IFN-gamma-inducible, STAT1-dependent genes such as IFN regulatory factor 1, IFN-gamma-inducible protein-10 (CXCL10), and monokine induced by IFN-gamma (CXCL9). IFN-alpha priming resulted in greatly enhanced STAT1 activation in response to IL-10, and STAT1 was required for IL-10 activation of IFN-gamma-inducible protein-10 and monokine induced by IFN-gamma expression in IFN-alpha-primed cells. In control, unprimed cells, IL-10 activation of STAT1 was suppressed by constitutive activity of protein kinase C and Src homology 2 domain-containing phosphatase 1. These results demonstrate that type I IFNs regulate the balance between IL-10 anti- and proinflammatory activity, and provide insight into molecular mechanisms that regulate IL-10 function. Gain of IL-10 proinflammatory functions may contribute to its pathogenic role in autoimmune diseases characterized by elevated type I IFN levels, such as systemic lupus erythematosus.
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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Animals
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Cells, Cultured
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Drug Synergism
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Humans
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Inflammation Mediators / antagonists & inhibitors
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Inflammation Mediators / physiology*
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Interferon-alpha / immunology*
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Interferon-alpha / pharmacology
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Interleukin-10 / antagonists & inhibitors
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Interleukin-10 / physiology*
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / immunology*
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Macrophage Activation / immunology
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Macrophage Colony-Stimulating Factor / pharmacology
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Knockout
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Mice, Mutant Strains
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Protein Kinase C / metabolism
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Protein Kinase C / physiology
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Protein Kinase C-delta
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Protein Phosphatase 1
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Protein Tyrosine Phosphatases / metabolism
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Protein Tyrosine Phosphatases / physiology
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STAT1 Transcription Factor
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Up-Regulation / immunology
Substances
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DNA-Binding Proteins
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Inflammation Mediators
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Interferon-alpha
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Lipopolysaccharides
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STAT1 Transcription Factor
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STAT1 protein, human
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Stat1 protein, mouse
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Trans-Activators
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Interleukin-10
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Macrophage Colony-Stimulating Factor
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Prkcd protein, mouse
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PRKCD protein, human
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Protein Kinase C
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Protein Kinase C-delta
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Protein Phosphatase 1
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Protein Tyrosine Phosphatases