Fc??receptor engagement by IgG is critical to activating myeloid cells during the inflammatory response. We find that IgG signaling requires Fyn kinase and is suppressed by Lyn. This is consistent in a model of Fc? receptor (Fc?R)-induced anaphylactic shock, where Lyn deletion exacerbates the response. We noted that Fc?R activated Stat5, whose deletion greatly reduced cytokine production. Fc?R responses are modified by cytokines. For example, IL-4 enhances inflammatory IgG receptor expression and cytokine secretion. In contrast, TGF?1 antagonizes cytokine production and selectively decreases Fyn and Stat5 expression. TGF?1 effects are absent in mast cells from Th2-prone mice, correlating with a lack of TGF-induced microRNAs capable of targeting Fyn and Stat5. We hypothesize that IL-4 and TGF?1 regulate IgG-mediated inflammation partly by controlling the Fyn/Lyn-Stat5 pathway. Dysregulated IgG-mediated signaling, perhaps due to genetically predisposed responses to cytokines, may serve as the etiologic origin of inflammatory arthritis. ! We will test this hypothesis with mechanistic experiments in vitro and functional assays in vivo.
Our Specific Aims are: I. To test the hypothesis that Fyn and Lyn provide antagonistic control of Fc?R signaling, including the Stat5 pathway. II. To test the hypothesis that Fc?R-mediated inflammation is controlled by a cytokine network that includes IL-4 and TGF?1. !
We will test the hypothesis that the kinases Fyn and Lyn provide antagonistic control of the critical transcription factor Stat5 during IgG-mediated signaling. This pathway can be regulated by cytokines, which collectively influence protective and pathological IgG responses, including those causing autoimmune arthritis.
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