PMID- 18089573
OWN - NLM
STAT- MEDLINE
DCOM- 20080410
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 8
DP  - 2008 Feb 22
TI  - 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.
PG  - 4643-51
AB  - 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.
FAU - Tanimoto, Akihide
AU  - Tanimoto A
AD  - 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
FAU - Murata, Yoshitaka
AU  - Murata Y
FAU - Wang, Ke-Yong
AU  - Wang KY
FAU - Tsutsui, Masato
AU  - Tsutsui M
FAU - Kohno, Kimitoshi
AU  - Kohno K
FAU - Sasaguri, Yasuyuki
AU  - Sasaguri Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20071218
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Heptanoic Acids)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Pyrroles)
RN  - 0 (RNA, Messenger)
RN  - 0 (STAT5 Transcription Factor)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - A0JWA85V8F (Atorvastatin)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
MH  - Atorvastatin
MH  - Chemokine CCL2/*biosynthesis/genetics/immunology
MH  - Down-Regulation/drug effects/genetics/immunology
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/genetics/immunology/*metabolism
MH  - Heptanoic Acids/*pharmacology
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
MH  - Inflammation/genetics/immunology/metabolism
MH  - Janus Kinase 2/genetics/immunology/*metabolism
MH  - Monocytes/immunology/*metabolism
MH  - Pyrroles/*pharmacology
MH  - RNA Stability/*drug effects/genetics/immunology
MH  - RNA, Messenger/biosynthesis/genetics/immunology
MH  - Response Elements/genetics/immunology
MH  - STAT5 Transcription Factor/genetics/immunology/*metabolism
MH  - Signal Transduction/*drug effects/genetics/immunology
MH  - Transcription, Genetic/drug effects/genetics/immunology
MH  - U937 Cells
MH  - Up-Regulation/*drug effects/genetics/immunology
EDAT- 2007/12/20 09:00
MHDA- 2008/04/11 09:00
CRDT- 2007/12/20 09:00
PHST- 2007/12/20 09:00 [pubmed]
PHST- 2008/04/11 09:00 [medline]
PHST- 2007/12/20 09:00 [entrez]
AID - S0021-9258(20)68225-4 [pii]
AID - 10.1074/jbc.M708853200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Feb 22;283(8):4643-51. doi: 10.1074/jbc.M708853200. Epub 2007 
      Dec 18.