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Priming Results in a Gain of Proinflammatory Function by IL-10: Implications for Systemic Lupus Erythematosus Pathogenesis1
,
* Arthritis and Tissue Degeneration Program and
Department of Medicine, Hospital for Special Surgery, New York, NY 10021;
Laboratory of Lymphocyte Signaling, Rockefeller University, New York, NY 10021; and Graduate Programs in
Immunology and
¶ Neuroscience, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021
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-
diminished the ability of IL-10 to suppress TNF- production. IFN- conferred a proinflammatory gain of function on IL-10, leading to IL-10 activation of expression of IFN-
-inducible, STAT1-dependent genes such as IFN regulatory factor 1, IFN--inducible protein-10 (CXCL10), and monokine induced by IFN- (CXCL9). IFN- priming resulted in greatly enhanced STAT1 activation in response to IL-10, and STAT1 was required for IL-10 activation of IFN--inducible protein-10 and monokine induced by IFN- expression in IFN--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.
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