Combined modulation of the mesangial machinery for monocyte recruitment by inhibition of NF-kappaB

Am J Physiol Cell Physiol. 2001 Dec;281(6):C1881-8. doi: 10.1152/ajpcell.2001.281.6.C1881.


The activation of nuclear factor-kappaB (NF-kappaB) is required for the induction of many of the adhesion molecules and chemokines involved in the inflammatory leukocyte recruitment to the kidney. Here we studied the effects of NF-kappaB inhibition on the machinery crucial for monocyte infiltration of the glomerulus during inflammation. In mesangial cells (MC), the protease inhibitors MG-132 and N-alpha-tosyl-L-lysine chloromethyl ketone or adenoviral overexpression of IkappaB-alpha prevented the complete IkappaB-alpha degradation following tumor necrosis factor-alpha (TNF-alpha) stimulation. This resulted in a marked inhibition of TNF-alpha-induced expression of mRNA and protein for the immunoglobulin molecules intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 and the chemokines growth-related oncogene-alpha, monocyte chemoattractant protein-1, interleukin-8, or fractalkine in MC. Finally, the inhibition of IkappaB-alpha degradation or IkappaB-alpha overexpression suppressed the chemokine-induced transendothelial monocyte chemotaxis toward MC and the chemokine-triggered firm adhesion of monocytic cells to MC. The inhibition of NF-kappaB by pharmacological intervention or gene transfer may present a multimodal approach to control the machinery propagating inflammatory recruitment of monocytes during glomerular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / physiology
  • Cell Movement / physiology
  • Cells, Cultured
  • Chemokines / genetics
  • Chemokines / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology
  • DNA-Binding Proteins / metabolism
  • Flow Cytometry
  • Glomerular Mesangium / cytology
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / metabolism*
  • Humans
  • I-kappa B Proteins*
  • Immunohistochemistry
  • Inflammation / physiopathology
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Leupeptins / pharmacology
  • Monocytes / metabolism*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Serine Proteinase Inhibitors / pharmacology
  • Tosyllysine Chloromethyl Ketone / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Chemokines
  • Cysteine Proteinase Inhibitors
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Leupeptins
  • NF-kappa B
  • NFKBIA protein, human
  • Serine Proteinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • NF-KappaB Inhibitor alpha
  • Tosyllysine Chloromethyl Ketone
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde