TNF-related activation-induced cytokine enhances leukocyte adhesiveness: induction of ICAM-1 and VCAM-1 via TNF receptor-associated factor and protein kinase C-dependent NF-kappaB activation in endothelial cells

J Immunol. 2005 Jul 1;175(1):531-40. doi: 10.4049/jimmunol.175.1.531.

Abstract

Inflammation is a basic pathological mechanism leading to a variety of vascular diseases. The inflammatory reaction involves complex interactions between both circulating and resident leukocytes and the vascular endothelium. In this study, we report evidence for a novel action of TNF-related activation-induced cytokine (TRANCE) as an inflammatory mediator and its underlying signaling mechanism in the vascular wall. TRANCE significantly increased endothelial-leukocyte cell interactions, and this effect was associated with increased expression of the cell adhesion molecules, ICAM-1 and VCAM-1, on the endothelial cells. RT-PCR analysis and promoter assays revealed that expression of these cell adhesion molecules was transcriptionally regulated mainly by activation of the inflammatory transcription factor, NF-kappaB. TRANCE induced IkappaB-alpha phosphorylation and NF-kappaB activation via a cascade of reactions involving the TNFR-associated factors, phospholipase C, PI3K, and protein kinase C (PKC-alpha and PKC-zeta). It also led to the production of reactive oxygen species via PKC- and PI3K-dependent activation of NADPH oxidase in the endothelial cells, and antioxidants suppressed the responses to TRANCE. These results demonstrate that TRANCE has an inflammatory action and may play a role in the pathogenesis of inflammation-related diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Carrier Proteins / immunology*
  • Carrier Proteins / pharmacology
  • Cell Adhesion / drug effects
  • Cells, Cultured
  • DNA / genetics
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism
  • Humans
  • I-kappa B Proteins / metabolism
  • Intercellular Adhesion Molecule-1 / biosynthesis*
  • Intercellular Adhesion Molecule-1 / genetics
  • Leukocytes / cytology
  • Leukocytes / drug effects
  • Leukocytes / immunology*
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / pharmacology
  • Models, Biological
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Kinase C / metabolism
  • RANK Ligand
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptor Activator of Nuclear Factor-kappa B
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • Transfection
  • U937 Cells
  • Vascular Cell Adhesion Molecule-1 / biosynthesis*
  • Vascular Cell Adhesion Molecule-1 / genetics

Substances

  • Carrier Proteins
  • I-kappa B Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • NFKBIA protein, human
  • RANK Ligand
  • RNA, Messenger
  • Reactive Oxygen Species
  • Receptor Activator of Nuclear Factor-kappa B
  • Recombinant Proteins
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 6
  • TNFRSF11A protein, human
  • TNFSF11 protein, human
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • NF-KappaB Inhibitor alpha
  • DNA
  • Protein Kinase C