ACTIVATION OF NUCLEAR FACTOR-KAPPA-B CORRELATES WITH MCP-1 EXPRESSION BY HUMAN MESANGIAL CELLS

Emerging evidence suggests that mesangial cell-derived monocyte chemoattractant protein-1 (MCP-1) is a potentially important mediator of glomerular monocyte infiltration. Interleukin-1 beta (IL-1) has been found in glomeruli during inflammation, and is a potent inducer of MCP-1 expression by mesangial cells. Analysis of the promoter region of the human MCP-1 gene demonstrates several putative binding sites for transcription activating factors, including recognition elements far the IL-1-inducible transcription factor, nuclear factor-kappa B (NF-kappa B). This study investigated the role of NF-kappa B in IL-1-induced MCP-1 expression by human mesangial cells. We found that treating mesangial cells with IL-1 resulted in the rapid activation within 30 min) and nuclear translocation of NF-kappa B. NF-kappa B activation could be blocked by preventing the proteolytic degradation of I kappa B, the cytoplasmic inhibitor of NF-kappa B, with the protease inhibitor tosyl-phe-chloromethylketone (TPCK). Inhibition of NF-kappa B with TPCK correlated with a dose-dependent reduction in IL-1-induced MCP-1 mRNA levels. Conversely, raising intracellular cyclic-AMP levels, or exposing mesangial cells to herbimycin A, treatments that block IL-1-induced MCP-1 mRNA expression, significantly attenuated NF-kappa B activation. Finally, blocking the synthesis of one of the protein subunits of NF-kappa B with an antisense oligonucleotide decreased MCP-1 mRNA levels in response to IL-1. These data suggest that MCP-1 gene transcription may be mediated, in part, by the transcription factor NF-kappa B.