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 for 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.
Rovin
B H
BH
Department of Medicine, Ohio State University School of Medicine, Columbus, USA.
Dickerson
J A
JA
Tan
L C
LC
Hebert
C A
CA
D000975:Antioxidants / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology
D000975:Antioxidants; D018932:Chemokine CCL2; D007375:Interleukin-1; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D014108:Tosylphenylalanyl Chloromethyl Ketone; D011392:Proline