TY - JOUR
T1 - 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
AU - De Keulenaer, Gilles W.
AU - Ushio-Fukai, Masuko
AU - Yin, Qi Qin
AU - Chung, Andrew B.
AU - Lyons, P. Reid
AU - Ishizaka, Nobukazu
AU - Rengarajan, Kalpana
AU - Taylor, W. Robert
AU - Alexander, R. Wayne
AU - Griendling, Kathy K.
PY - 2000/2
Y1 - 2000/2
N2 - 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.
AB - 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.
KW - Cytokines
KW - Monocyte chemoattractant protein-1
KW - Reactive oxygen species
KW - Smooth muscle cells
KW - Tyrosine kinase
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U2 - 10.1161/01.ATV.20.2.385
DO - 10.1161/01.ATV.20.2.385
M3 - Article
C2 - 10669634
AN - SCOPUS:0033972465
SN - 1079-5642
VL - 20
SP - 385
EP - 391
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 2
ER -