on January 25, 2007
Published online before print January 25, 2007, doi: 10.1161/01.ATV.0000258867.79411.96
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Submitted on September 15, 2006
Accepted on January 9, 2007
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 ;
From the Cardiff School of Biosciences, Cardiff University, UK.
* To whom correspondence should be addressed. 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 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.
Key words: atherosclerosis • chemokines • gene expression • INF-gamma • macrophage • monocyte chemoattractant protein-1 • signal transduction
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