Critical role for casein kinase 2 and phosphoinositide-3-kinase in the interferon-gamma-induced expression of monocyte chemoattractant protein-1 and other key genes implicated in atherosclerosis.
OBJECTIVE
The interferon-gamma (IFN-gamma)-mediated regulation of macrophage gene expression is of crucial importance in the pathogenesis of atherosclerosis. The mechanisms underlying the actions of IFN-gamma signaling in macrophages were investigated using monocyte chemoattractant protein (MCP)-1 as a model gene.


RESULTS
The IFN-gamma-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-gamma responsive elements in the MCP-1 gene promoter. The IFN-gamma-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-gamma signaling.


CONCLUSIONS
These studies provide novel insights into the role of PI3K/AKT and CK2 in IFN-gamma signaling relevant to changes in macrophage gene expression during atherosclerosis.
Harvey
Elizabeth J
EJ
Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK.
Li
Na
N
Ramji
Dipak P
DP
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D047390:Casein Kinase II; D018932:Chemokine CCL2; D007371:Interferon-gamma; D053612:Janus Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D050794:STAT1 Transcription Factor