Monocyte chemoattractant protein-1 expression is enhanced by granulocyte-macrophage colony-stimulating factor via Jak2-Stat5 signaling and inhibited by atorvastatin in human monocytic U937 cells.
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.
Tanimoto
Akihide
A
Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. aki@med.uoeh-u.ac.jp
Murata
Yoshitaka
Y
Wang
Ke-Yong
KY
Tsutsui
Masato
M
Kohno
Kimitoshi
K
Sasaguri
Yasuyuki
Y
D000069059:Atorvastatin; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D020871:RNA Stability / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020218:Response Elements / Q000235:genetics / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000069059:Atorvastatin; C507924:JAK2 protein, human; D053614:Janus Kinase 2