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

Abstract

Abstract-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-␣ (TNF-␣). 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-␣ 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 (43Ϯ10% inhibition). Incubation of VSMCs with multiple antioxidants (diphenylene iodonium, liposomal superoxide dismutase, catalase, N-acetylcysteine, dimethylthiourea, and pyrrolidine dithiocarbamate) had no effect on TNF-␣-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 (100Ϯ2% inhibition). Thus, parallel ROS-dependent and ERK1/2-dependent pathways converge to regulate TNF-␣-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.

Uric Acid Stimulates Monocyte Chemoattractant Protein-1 Production in Vascular Smooth Muscle Cells Via Mitogen-Activated Protein Kinase and Cyclooxygenase-2

“…[22][23][24][25] The ability to activate p38 MAPK, NF-kB, and AP-1, as well as to increase MCP-1 expression, is consistent with an oxidantdriven pathway. 26,27 In conclusion, we have found that uric acid can induce inflammatory pathways in rat VSMCs in vitro, with activation of p38 MAPK, NF-B, and AP-1 and increased expression of COX-2 and MCP-1. Although the inflammatory potential of crystalline uric acid has been well known, this study provides the first evidence that soluble uric acid can also engage these pathways.…”

Neutrophils responsive to endogenous IFN-β regulate tumor angiogenesis and growth in a mouse tumor model

“…CCL2 is additionally known to be a potent chemoattractant for myeloid cells, such as monocytes and neutrophils (39,(50)(51)(52)(53)(54). It is believed to be produced by various cells, including vascular smooth muscle cells (55,56). This may explain the higher content of this chemokine in the highly vascularized melanoma tumors from Ifnb1 -/-mice.…”

The role of peroxidases in the pathogenesis of atherosclerosis

“…In addition, ROS produced via NAD(P)H oxidase induce VSMCs to produce and secrete matrix metalloproteinases involved in the degradation and reorganization of the extracellular matrix (74,75). In VSMCs, ROS also mediate inflammation (e.g., MCP-1 expression via TNF-α) (76) and apoptosis via p53 and Bax/Bad (77). http://bmbreports.org …”