IFN-β-induced IL-1Ra synthesis in human monocytes involves PI 3-kinase-STAT1 signaling pathway

IFN-β displays an anti-inflammatory property by inducing IL-1Ra without triggering synthesis of IL-1β in human monocytes (Mo). IFN-β initiates JAK-STAT pathway that may cross-talk with components of MAP- and PI 3-kinase pathways. Since maximal activation of transcription by several STATs requires both Tyr and Ser phosphorylation, we investigated the role of MAP- (ERK1/2) and PI 3-kinases in IFN-β-induced IL-1Ra production in Mo. The PI 3-kinase inhibitor Ly294002 but not the MAP kinase inhibitor PD98052 suppresses, in a dose-dependent way, IL-1Ra production in Mo at a protein level correlating with the reduction of steady state levels of IL-1Ra mRNA. IFN-β treatment of Mo leads to rapid Ser-phosphorylation and nuclear translocation of STAT1 that is inhibited by Ly294002. Interestingly, suppression of PI 3-kinase activity in Mo stimulated by IFN-β and anti-CD11b mAb results in inhibition of IL-1Ra and upregulation of IL-1β production, suggesting that PI 3-kinase might be a check-point signaling molecule favoring IL-1Ra synthesis. Involvement of PI 3-kinase pathway in IL-1Ra synthesis seems to be independent of the differentiation state of Mo: M-CSF differentiated Mo requires activation of PI 3-kinase to synthesize IL-1Ra following IFN-β treatment. Thus, IFN-β induced IL-1Ra production in Mo by simultaneously activating components of JAK-STAT and PI 3-kinase signaling pathways.