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CARDIOVASCULAR

Dual Regulation of Tumor Necrosis Factor--Induced CCL2/Monocyte Chemoattractant Protein-1 Expression in Vascular Smooth Muscle Cells by Nuclear Factor-B and Activator Protein-1: Modulation by Type III Phosphodiesterase Inhibition

Department of Medicine, National Taiwan University Hospital and College of Medicine National Taiwan University, Taipei, Taiwan

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)- 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--induced CCL2/MCP-1 production, without affecting I-B degradation or p65/nuclear factor-B (NF-B) nuclear translocation. PD98059 abolished TNF--activated p42/44 MAPK phosphorylation and c-Fos up-regulation, whereas SP600125 inhibited TNF--activated JNK and c-Jun phosphorylation. The NF-B inhibitor carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132) attenuated TNF--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--induced CCL2/MCP-1 production. Finally, the pretreatment of VSMCs with PTX or cilostamide, but not denbufylline, reduced TNF--induced CCL2/MCP-1 production, which was preceded by attenuation of p65/NF-B nuclear translocation, p42/44 MAPK, and JNK-c-Jun phosphorylation, and c-Fos up-regulation. These data indicate that TNF--stimulated CCL2/MCP-1 production in rat VSMCs is dually regulated by activator protein-1 (AP-1) and NF-B 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-B signals.

Address correspondence to: Dr. Kwan-Dun Wu, Department of Medicine, National Taiwan University Hospital, 7, Chung-Shan South Rd., Taipei, 10016, Taiwan. E-mail: kdw{at}ha.mc.ntu.edu.tw.

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