Combined modulation of the mesangial machinery for monocyte recruitment byinhibition of NF-kappa B

The activation of nuclear factor-kappaB (NF-kappaB) is required for the ind uction of many of the adhesion molecules and chemokines involved in the inf lammatory 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 proteas e inhibitors MG-132 and N-alpha -tosyl-L-lysine chloromethyl ketone or aden oviral overexpression of I kappaB-alpha prevented the complete I kappaB-alp ha degradation following tumor necrosis factor-alpha (TNF-alpha) stimulatio n. This resulted in a marked inhibition of TNF-alpha -induced expression of mRNA and protein for the immunoglobulin molecules intracellular adhesion m olecule-1 and vascular cell adhesion molecule-1 and the chemokines growth-r elated oncogene-alpha, monocyte chemoattractant protein-1, interleukin-8, o r fractalkine in MC. Finally, the inhibition of IkB-alpha degradation or Ik B-alpha overexpression suppressed the chemokine-induced transendothelial mo nocyte chemotaxis toward MC and the chemokine-triggered firm adhesion of mo nocytic cells to MC. The inhibition of NF-kappaB by pharmacological interve ntion or gene transfer may present a multimodal approach to control the mac hinery propagating inflammatory recruitment of monocytes during glomerular disease.