c-Rel and p65 trans-activate the monocyte chemoattractant protein-1 gene in interleukin-1 stimulated mesangial cells

Kidney Int. 1999 Sep;56(3):873-82. doi: 10.1046/j.1523-1755.1999.00640.x.

Abstract

Background: The chemokine monocyte chemoattractant protein-1 (MCP-1) is secreted by human glomerular mesangial cells in response to interleukin-1 (IL-1) and has a central role in amplifying the inflammatory response during glomerulonephritis. However, the mechanism by which IL-1 regulates its transcription is not understood. Specific members of the nuclear factor kappaB/rel (NF-kappaB) proteins may regulate MCP-1 expression in a stimulus- and tissue-specific manner.

Methods: Electrophoretic mobility shift assays and Western blot analysis characterized the members of the NF-kappaB family that bound the two NF-kappaB sites of the MCP-1 enhancer (A1 and A2) in vitro. Trans-activation of the MCP-1 gene was investigated by transfer of the MCP-1 enhancer DNA to mesangial cells.

Results: Primary human mesangial cells contained in addition to p50 (NF-kappaB1) and p65 (Rel A) NF-kappaB proteins, the oncoprotein c-rel, and Rel B, but not p52 (NF-kappaB2). IL-1 induced c-rel to form a complex with p65, which bound the MCP-1 A2 site but not the A1 or IL-6 NF-kappaB sites in vitro. IL-1 up-regulated transfected MCP-1 enhancer activity. Cotransfer of the MCP-1 enhancer together with individual members of the NF-kappaB family showed that the heterodimer c-relp65 or (p65)2 can selectively trans-activate the MCP-1 gene via its A1 and A2 sites in mesangial cells.

Conclusions: This study demonstrates for the first time that the c-rel oncoprotein can enhance MCP-1 transcription in mesangial cells and suggests that it may have an important role in amplifying gene expression in the inflamed glomerulus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites / genetics
  • Cells, Cultured
  • Chemokine CCL2 / genetics*
  • Enhancer Elements, Genetic
  • Glomerular Mesangium / cytology
  • Glomerular Mesangium / drug effects*
  • Glomerular Mesangium / metabolism*
  • Humans
  • Interleukin-1 / pharmacology*
  • Interleukin-6 / genetics
  • Ligases / metabolism*
  • NF-kappa B / metabolism
  • Oligonucleotide Probes / genetics
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-rel
  • Rats
  • Transcription Factor RelB
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Transfection

Substances

  • Chemokine CCL2
  • Interleukin-1
  • Interleukin-6
  • NF-kappa B
  • Oligonucleotide Probes
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-rel
  • RELB protein, human
  • Relb protein, rat
  • Transcription Factors
  • Transcription Factor RelB
  • Ligases
  • guanosine 3',5'-polyphosphate synthetases