Combined modulation of the mesangial machinery for monocyte recruitment by inhibition of NF-kappaB.
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.
Zernecke
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Institute for Prevention of Cardiovascular Disease, Ludwig-Maximilians Universität München, D-80336 Munich, Germany.
Weber
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Weber
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D000256:Adenoviridae / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D007150:Immunohistochemistry; D007249:Inflammation / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014107:Tosyllysine Chloromethyl Ketone / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D018925:Chemokines; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007976:Leupeptins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D014107:Tosyllysine Chloromethyl Ketone; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde