PT  - JOURNAL ARTICLE
AU  - Yung-Ming Chen
AU  - Wen-Chih Chiang
AU  - Shuei-Liong Lin
AU  - Kwan-Dun Wu
AU  - Tun-Jun Tsai
AU  - Bor-Shen Hsieh
TI  - Dual Regulation of Tumor Necrosis Factor-α-Induced CCL2/Monocyte Chemoattractant Protein-1 Expression in Vascular Smooth Muscle Cells by Nuclear Factor-κB and Activator Protein-1: Modulation by Type III Phosphodiesterase Inhibition
AID  - 10.1124/jpet.103.062620
DP  - 2004 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 978--986
VI  - 309
IP  - 3
4099  - http://jpet.aspetjournals.org/content/309/3/978.short
4100  - http://jpet.aspetjournals.org/content/309/3/978.full
SO  - J Pharmacol Exp Ther2004 Jun 01; 309
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)-α 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 NH2-terminal kinases (JNKs)] attenuated TNF-α-induced CCL2/MCP-1 production, without affecting I-κBα degradation or p65/nuclear factor-κB (NF-κB) nuclear translocation. PD98059 abolished TNF-α-activated p42/44 MAPK phosphorylation and c-Fos up-regulation, whereas SP600125 inhibited TNF-α-activated JNK and c-Jun phosphorylation. The NF-κB inhibitor carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (MG132) attenuated TNF-α-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-α-induced CCL2/MCP-1 production. Finally, the pretreatment of VSMCs with PTX or cilostamide, but not denbufylline, reduced TNF-α-induced CCL2/MCP-1 production, which was preceded by attenuation of p65/NF-κB nuclear translocation, p42/44 MAPK, and JNK-c-Jun phosphorylation, and c-Fos up-regulation. These data indicate that TNF-α-stimulated CCL2/MCP-1 production in rat VSMCs is dually regulated by activator protein-1 (AP-1) and NF-κB 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-κB signals. The American Society for Pharmacology and Experimental Therapeutics