TNFR1-induced NF-kappa B, but not ERK, p38MAPK or JNK activation, mediates TNF-induced ICAM-1 and VCAM-1 expression on endothelial cells

Zhigang Zhou, Michelle C. Connell, David J. MacEwan

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166 Citations (SciVal)

Abstract

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine, whose primary targets include vascular endothelial cells. TNF-mediated adhesion molecule expression has been shown to play a central role in endothelial cells inflammatory responses and disorders such as atherosclerosis. However it is not fully understand how the TNF receptor subtypes, namely TNFR1 and TNFR2, regulate inflammatory responses in endothelial cells. The aim of this study was to elucidate the kinase signalling pathways that TNF receptors activate, and determine the pathways responsible for downstream expression of adhesion molecules, intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human endothelial cells. Using human umbilical vein endothelial cells (HUVEC), we demonstrated that TNF activates a range of mitogen-activated protein kinases (MAPKs), including the extracellular-regulated kinase (ERK) pathway and the p38MAPK and c-Jun N-terminal kinase (JNK) stress kinase pathways. Human endothelial cells express both TNF receptor subtypes at low levels, however using TNFR-specific agonistic agents, we uncovered that TNF acts through its TNFR1 receptor subtype to activate NF-kappa B transcriptional pathways. Further investigation revealed that ICAM-1 and VCAM-I mRNA and protein are induced by TNFR1 (but not TNFR2) in a wholly NF-kappa B-dependent manner. These findings reveal for the first time that TNF stimulation of adhesion molecules ICAM-I and VCAM-I in human endothelial cells occurs through the TNFR1 subtype and is mediated by the NF-kappa B pathway, but not the ERK, p38MAPK or INK kinase pathways. (c) 2007 Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)1238-1248
Number of pages11
JournalCellular Signalling
Volume19
Issue number6
DOIs
Publication statusPublished - Jun 2007

Keywords

  • cytokine
  • receptor
  • subtypes
  • cell signalling
  • endothelium
  • adhesion molecule

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