Convergence of redox-sensitive and mitogen-activated protein kinase signaling pathways in tumor necrosis factor-α-mediated monocyte chemoattractant protein-1 induction in vascular smooth muscle cells

Gilles W. De Keulenaer, Masuko Ushio-Fukai, Qi Qin Yin, Andrew B. Chung, P. Reid Lyons, Nobukazu Ishizaka, Kalpana Rengarajan, W. Robert Taylor, R. Wayne Alexander, Kathy K. Griendling

Research output: Contribution to journalArticle

87 Scopus citations


Monocyte chemoattractant protein-1 (MCP-1) is an important component of the inflammatory response of the vessel wall and has been shown to be regulated by cytokines, such as tumor necrosis factor-α (TNF-α). However, the precise signaling pathways leading to MCP-1 induction have not been fully elucidated in vascular smooth muscle cells (VSMCs). Cytokine signal transduction involves protein kinases as well as reactive oxygen species (ROS). The relation between these 2 factors is not clear. In this study, we show that TNF-α induces a parallel phosphorylation of extracellular signal- regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) and increases MCP-1 mRNA expression in cultured VSMCs. Inhibition of ERK1/2 but not p38MAPK caused a partial attenuation of MCP-1 induction (43±10% inhibition). Incubation of VSMCs with multiple antioxidants (diphenylene iodonium, liposomal superoxide dismutase, catalase, N- acetylcysteine, dimethylthiourea, and pyrrolidine dithiocarbamate) had no effect on TNF-α-mediated MCP-1 upregulation. However, simultaneous blockade of the ERK1/2 and ROS pathways by using PD098059 combined with diphenylene iodonium or N-acetylcysteine potently enhanced the ability of MAPK kinase inhibitors to abrogate MCP-1 mRNA expression (100±2% inhibition). Thus, parallel ROS-dependent-and ERK1/2-dependent pathways converge to regulate TNF-α-induced MCP-1 gene expression in VSMCs. These data unmask a complex but organized integration of ROS and protein kinases that mediates cytokine- induced vascular inflammatory gene expression.

Original languageEnglish (US)
Pages (from-to)385-391
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number2
Publication statusPublished - Feb 2000
Externally publishedYes



  • Cytokines
  • Monocyte chemoattractant protein-1
  • Reactive oxygen species
  • Smooth muscle cells
  • Tyrosine kinase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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