IFN-alpha priming results in a gain of proinflammatory function by IL-10: implications for systemic lupus erythematosus pathogenesis.
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.
Sharif
M Nusrat
MN
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
Tassiulas
Ioannis
I
Hu
Yang
Y
Mecklenbräuker
Ingrid
I
Tarakhovsky
Alexander
A
Ivashkiv
Lionel B
LB
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D016898:Interferon-alpha / Q000276:immunology* / Q000494:pharmacology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology; D051745:Protein Kinase C-delta; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D016753:Interleukin-10; D016173:Macrophage Colony-Stimulating Factor; C497259:Prkcd protein, mouse; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases