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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:806.)
© 2007 American Heart Association, Inc.

Vascular Biology

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

Elizabeth J. Harvey; Na Li; Dipak P. Ramji

From the Cardiff School of Biosciences, Cardiff University, UK.

Correspondence to Dipak P. Ramji, Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK. E-mail Ramji{at}cardiff.ac.uk

Objective— The interferon- (IFN-)–mediated regulation of macrophage gene expression is of crucial importance in the pathogenesis of atherosclerosis. The mechanisms underlying the actions of IFN- signaling in macrophages were investigated using monocyte chemoattractant protein (MCP)-1 as a model gene.

Methods and Results— The IFN-–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- responsive elements in the MCP-1 gene promoter. The IFN-–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- signaling.

Conclusions— These studies provide novel insights into the role of PI3K/AKT and CK2 in IFN- signaling relevant to changes in macrophage gene expression during atherosclerosis.

The mechanisms underlying the IFN-–regulated expression of monocyte chemoattractant protein-1 and other key genes implicated in atherosclerosis were investigated. We show critical roles for CK2 and PI3K in addition to the JAK/STAT pathway in IFN-–signaling in macrophages, which have implications in the development of atherosclerosis.

Key Words: atherosclerosis • chemokines • gene expression • IFN-gamma • macrophage • monocyte chemoattractant protein-1 • signal transduction

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