Abstract
The proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is expressed in inflammatory and atherosclerotic lesions. GM-CSF is known to enhance monocytic expression of monocyte chemoattractant protein-1 (MCP-1). However, the molecular mechanism(s) by which GM-CSF up-regulates the MCP-1 expression remains to be clarified. Thus, in this study, we examined our hypothesis that GM-CSF up-regulates the MCP-1 expression via Jak2-Stat5 signaling pathway. In human monocytic cell line U937, GM-CSF increased MCP-1 expression in protein and mRNA levels. Furthermore, analysis of the GM-CSF promoter element revealed that the STAT5 (signal transducer and activator of transcription-5) transcription factor binding site, located between -152 and -144 upstream of the transcription start site, as well as Janus kinase-2-mediated Stat5 activation were necessary for the GM-CSF-induced transcriptional up-regulation of the MCP-1 gene. This GM-CSF-induced MCP-1 expression, measured as both protein and mRNA levels, was down-regulated by atorvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. However, this decrease in MCP-1 expression was not at the transcriptional level of MCP-1 gene but rather at the level of the stability of MCP-1 mRNA. These results indicate that GM-CSF regulates MCP-1 expression via Janus kinase-2-Stat5 pathway and by a novel regulatory mechanism of statins to reduce inflammatory reactions by down-regulating the expression of monocytic MCP-1, which promotes atherogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Atorvastatin
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Chemokine CCL2 / biosynthesis*
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Chemokine CCL2 / genetics
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Chemokine CCL2 / immunology
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Down-Regulation / immunology
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Granulocyte-Macrophage Colony-Stimulating Factor / genetics
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Granulocyte-Macrophage Colony-Stimulating Factor / immunology
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
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Heptanoic Acids / pharmacology*
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / metabolism
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Janus Kinase 2 / genetics
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Janus Kinase 2 / immunology
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Janus Kinase 2 / metabolism*
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Monocytes / immunology
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Monocytes / metabolism*
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Pyrroles / pharmacology*
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RNA Stability / drug effects*
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RNA Stability / genetics
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RNA Stability / immunology
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Messenger / immunology
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Response Elements / genetics
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Response Elements / immunology
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / immunology
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STAT5 Transcription Factor / metabolism*
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Signal Transduction / immunology
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Transcription, Genetic / drug effects
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Transcription, Genetic / genetics
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Transcription, Genetic / immunology
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U937 Cells
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Up-Regulation / drug effects*
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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CCL2 protein, human
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Chemokine CCL2
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Heptanoic Acids
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Pyrroles
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RNA, Messenger
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STAT5 Transcription Factor
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Granulocyte-Macrophage Colony-Stimulating Factor
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Atorvastatin
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JAK2 protein, human
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Janus Kinase 2