The Role of Glycogen Synthase Kinase 3 in Regulating IFN-β-Mediated IL-10 Production

The ability of IFN-beta to induce IL-10 production from innate immune cells is important for its anti-inflammatory properties and is believed to contribute to its therapeutic value in treating multiple sclerosis patients. In this study, we identified that IFN-beta stimulates IL-10 production by activating the JAK1- and PI3K-signaling pathways. JAK1 activity was required for IFN-beta to activate PI3K and Akt1 that resulted in repression of glycogen synthase kinase 3 (GSK3)-beta activity. IFN-beta-mediated suppression of GSK3-beta promoted IL-10, because IL-10 production by IFN-beta-stimulated dendritic cells (DC) expressing an active GSK3-beta knockin was severely reduced, whereas pharmacological or genetic inhibition of GSK3-b augmented IL-10 production. IFN-beta increased the phosphorylated levels of CREB and STAT3 but only CREB levels were affected by PI3K. Also, a knockdown in CREB, but not STAT3, affected the capacity of IFN-beta to induce IL-10 from DC. IL-10 production by IFN-beta-stimulated DC was shown to suppress IFN-gamma and IL-17 production by myelin oligodendrocyte glycoprotein-specific CD4(+) T cells, and this IL-10-dependent anti-inflammatory effect was enhanced by directly targeting GSK3 in DC. These findings highlight how IFN-beta induces IL-10 production and the importance that IL-10 plays in its anti-inflammatory properties, as well as identify a therapeutic target that could be used to increase the IL-10-dependent anti-inflammatory properties of IFN-beta. The Journal of Immunology, 2011, 186: 675-684.