PMID- 14978197
OWN - NLM
STAT- MEDLINE
DCOM- 20040701
LR  - 20091119
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 309
IP  - 3
DP  - 2004 Jun
TI  - Dual regulation of tumor necrosis factor-alpha-induced CCL2/monocyte 
      chemoattractant protein-1 expression in vascular smooth muscle cells by nuclear 
      factor-kappaB and activator protein-1: modulation by type III phosphodiesterase 
      inhibition.
PG  - 978-86
AB  - Monocyte/macrophage infiltration to the subendothelial space of arterial wall is 
      a critical initial step in atherogenesis, in which CC chemokine ligand 2 
      (CCL2)/monocyte chemoattractant protein-1 (MCP-1) is thought to play a key role. 
      This study investigated the effectiveness of phosphodiesterase inhibitors, 
      including the nonselective pentoxifylline (PTX) and the selective type III 
      (cilostamide) and type IV (denbufylline) inhibitors, on cytokine-induced 
      CCL2/MCP-1 production in cultured rat vascular smooth muscle cells (VSMCs), and 
      the signal transduction mechanisms whereby they act. Our results showed that 
      tumor necrosis factor (TNF)-alpha induced a marked increase in CCL2/MCP-1 
      production in dose- and time-dependent manners. 
      2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059), 
      1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio) butadiene (U0126) [both 
      inhibitors of p42/44 mitogen-activated protein kinase (MAPK) kinase], and 
      anthra[1hyphen]9-cd]pyrazol-6(2H)-one (SP600125) [an inhibitor of c-Jun 
      NH(2)-terminal kinases (JNKs)] attenuated TNF-alpha-induced CCL2/MCP-1 
      production, without affecting I-kappaBalpha degradation or p65/nuclear 
      factor-kappaB (NF-kappaB) nuclear translocation. PD98059 abolished 
      TNF-alpha-activated p42/44 MAPK phosphorylation and c-Fos up-regulation, whereas 
      SP600125 inhibited TNF-alpha-activated JNK and c-Jun phosphorylation. The 
      NF-kappaB inhibitor carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (MG132) attenuated 
      TNF-alpha-induced CCL2/MCP-1 production in the presence of increased phospho-JNK 
      and phospho-c-Jun levels. When SP600125 was added simultaneously, MG132 
      completely inhibited TNF-alpha-induced CCL2/MCP-1 production. Finally, the 
      pretreatment of VSMCs with PTX or cilostamide, but not denbufylline, reduced 
      TNF-alpha-induced CCL2/MCP-1 production, which was preceded by attenuation of 
      p65/NF-kappaB nuclear translocation, p42/44 MAPK, and JNK-c-Jun phosphorylation, 
      and c-Fos up-regulation. These data indicate that TNF-alpha-stimulated CCL2/MCP-1 
      production in rat VSMCs is dually regulated by activator protein-1 (AP-1) and 
      NF-kappaB pathways, and inhibition of type III phosphodiesterase contributes 
      substantially to the suppressive effect of PTX on CCL2/MCP-1 production via 
      down-regulation of AP-1 and NF-kappaB signals.
FAU - Chen, Yung-Ming
AU  - Chen YM
AD  - Department of Medicine, National Taiwan University Hospital, 7, Chung-Shan South 
      Rd., Taipei, 10016, Taiwan.
FAU - Chiang, Wen-Chih
AU  - Chiang WC
FAU - Lin, Shuei-Liong
AU  - Lin SL
FAU - Wu, Kwan-Dun
AU  - Wu KD
FAU - Tsai, Tun-Jun
AU  - Tsai TJ
FAU - Hsieh, Bor-Shen
AU  - Hsieh BS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20040220
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Ccl2 protein, rat)
RN  - 0 (Chemokine CCL2)
RN  - 0 (NF-kappa B)
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
SB  - IM
MH  - 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors/*metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Chemokine CCL2/genetics/*metabolism
MH  - Cyclic Nucleotide Phosphodiesterases, Type 3
MH  - Gene Expression/drug effects
MH  - Male
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Muscle, Smooth, Vascular/metabolism
MH  - NF-kappa B/*physiology
MH  - Phosphodiesterase Inhibitors/pharmacology
MH  - Proteins/genetics/*metabolism
MH  - RNA, Messenger/drug effects/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Transcription Factor AP-1/*physiology
MH  - Tumor Necrosis Factor-alpha/genetics/*metabolism
EDAT- 2004/02/24 05:00
MHDA- 2004/07/02 05:00
CRDT- 2004/02/24 05:00
PHST- 2004/02/24 05:00 [pubmed]
PHST- 2004/07/02 05:00 [medline]
PHST- 2004/02/24 05:00 [entrez]
AID - jpet.103.062620 [pii]
AID - 10.1124/jpet.103.062620 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2004 Jun;309(3):978-86. doi: 10.1124/jpet.103.062620. Epub 
      2004 Feb 20.