The type I interferons (IFNs), IFNa and IFN?, are highly expressed in systemic lupus erythematosus (SLE) and have been implicated in the pathogenesis of human SLE and in murine models. There is great interest in type I IFNs as pathogenic factors and therapeutic targets in SLE, although type I IFNs may also have some protective effects in SLE. Evidence to date indicates that type I IFNs impact upon SLE pathogenesis by regulating the development of autoimmunity and autoantibody production. Less is known about the effects of type I IFNs on the effector inflammatory phase of SLE, which is an area of interest of our lab. A key aspect of IFN biology is that previous exposure to type I IFNs alters subsequent cellular responses to extracellular stimuli. We hypothesized that alteration of macrophage responses to cytokines and inflammatory factors represents a molecular mechanism by which type I IFNs promote macrophage activation at sites of inflammation, and thereby contribute to SLE pathogenesis. To test this hypothesis, we examined the effects of type I IFNs on cellular responses to IL-10 and immune complexes, factors that are highly expressed in SLE and have been implicated in pathogenesis. IL-10 is a predominantly immunosuppressive and anti-inflammatory cytokine that inhibits macrophage function, but, paradoxically, has been implicated in SLE pathogenesis. We found that pretreatment with IFNa altered IL-10 signal transduction, increasing IL-10 activation of the transcription factor Stat1 (typically activated by IFNy) and resulting in IL-10 activation of """"""""IFNy-inducible genes"""""""", including the chemokines CXCL9 (Mig) and CXCL10 (IP-10). We hypothesize that IFNa """"""""reprogramming"""""""" of IL-10 signaling, such that IL-10 activates chemokine expression and subsequent recruitment of cells to inflammatory sites, represents one mechanism by which IL-10 contributes to SLE pathogenesis. Immune complexes activate macrophage effector functions, including cytokine production, by ligation of cell surface FcyRs and are important in driving inflammation in SLE. IFNa altered cellular responses to immune complexes, such that FcyR-induced production of TNFa, which regulates both autoimmunity and inflammation, was suppressed. Thus, we propose that understanding mechanisms by which IFNs regulate FcyR function and downstream TNFa production is important for understanding the role of IFNs in SLE. In this proposal, we will investigate the molecular mechanisms and (patho) physiological significance of IFNa-induced alterations in IL-10 and FcyR action. These experiments will yield insight into the molecular pathogenesis of SLE and identify novel therapeutic approaches to manipulate cytokine activity in SLE at the level of signal transduction. ? ?
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