Critical role for casein kinase 2 and phosphoinositide-3-kinase in the interferon- -induced expression of monocyte chemoattractant protein-1 and other key genes implicated in atherosclerosis

Objective— The interferon-γ (IFN-γ)–mediated regulation of macrophage gene expression is of crucial importance in the pathogenesis of atherosclerosis. The mechanisms underlying the actions of IFN-γ signaling in macrophages were investigated using monocyte chemoattractant protein (MCP)-1 as a model gene. Methods and Results— The IFN-γ–induced expression of MCP-1 in macrophages was attenuated by inhibitors of phosphoinositide-3-kinase (PI3K), casein kinase 2 (CK2), and Janus kinase (JAK)-2. AKT was the downstream target for PI3K action. Electrophoretic mobility shift assays and chromatin immunoprecipitation showed that signal transducer and activator of transcription (STAT)-1 interacted with IFN-γ responsive elements in the MCP-1 gene promoter. The IFN-γ–induced activity of the MCP-1 gene promoter and an artificial promoter containing STAT1 responsive elements was inhibited by expression of dominant negative forms of JAK-1 and -2, STAT1, CK2, and AKT. The action of CK2 and AKT on STAT1 activation was mediated, at least in part, through the regulation of serine 727 phosphorylation. Analysis of a number of other genes regulated by this cytokine and implicated in atherosclerosis revealed a gene-specific action for PI3K/AKT in IFN-γ signaling. Conclusions— These studies provide novel insights into the role of PI3K/AKT and CK2 in IFN-γ signaling relevant to changes in macrophage gene expression during atherosclerosis