Laboratory Investigation

Kidney International (1995) 48, 1263–1271; doi:10.1038/ki.1995.410

Activation of nuclear factor-kappaB correlates with MCP-1 expression by human mesangial cells

Brad H Rovin1, Jennifer A Dickerson1, Laura C Tan1 and Caroline A Hebert1

1Departments of Medicine and Pathology, Ohio State University School of Medicine, Columbus, Ohio, USA

Correspondence: Brad H Rovin MD, Nephrology Division, Ohio State University, 2-North Means Hall, 1654 Upham Drive, Columbus, Ohio 43210, USA.

Received 28 November 1994; Revised 12 May 1995; Accepted 15 May 1995.

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Abstract

Activation of nuclear factor-kappaB 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-1beta (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 for the IL-1-inducible transcription factor, nuclear factor-kappa B (NF-kappaB). This study investigated the role of NF-kappaB 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-kappaB. NF-kappaB activation could be blocked by preventing the proteolytic degradation of IkappaB, the cytoplasmic inhibitor of NF-kappaB, with the protease inhibitor tosyl-phe-chloromethylketone (TPCK). Inhibition of NF-kappaB 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-kappaB activation. Finally, blocking the synthesis of one of the protein subunits of NF-kappaB 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-kappaB.

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