Differential activation of NF-kappa B, AP-1, and C/EBP in endotoxin-tolerant rats: mechanisms for in vivo regulation of glomerular RANTES/CCL5 expression

J Immunol. 2003 Jun 15;170(12):6280-91. doi: 10.4049/jimmunol.170.12.6280.

Abstract

Chemokines play a pivotal role in the regulation of inflammatory cell infiltration in glomerular immune injury. To characterize mechanisms relevant for the regulation of chemokine expression in vivo, the LPS-mediated model of renal inflammation in rats was used in which we have previously demonstrated that the chemokine RANTES/CCL5 is expressed and secreted in glomeruli. Glomerular RANTES/CCL5 expression in this model correlated with an increased glomerular binding activity of the transcription factors AP-1, C/EBP, and NF-kappaB. To gain further insight into the functional roles of these transcription factors in the regulation of glomerular RANTES/CCL5 expression, we cloned the rat RANTES/CCL5 promoter and established the model of in vivo LPS tolerance. In tolerant rats, LPS-induced glomerular RANTES/CCL5 expression and activation of the transcription factors AP-1 and C/EBP were significantly reduced using both consensus and rat RANTES/CCL5-specific oligonucleotides. Reduced glomerular NF-kappaB binding activity after LPS injection could be demonstrated in tolerant rats only when using rat RANTES/CCL5-specific oligonucleotides. Reduced binding activity to this RANTES/CCL5-specific NF-kappaB binding site in the context of broad NF-kappaB activation might be due to changes in transcription factor interactions or chromatin remodeling processes.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites / genetics
  • Binding Sites / immunology
  • Binding, Competitive / genetics
  • Binding, Competitive / immunology
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Chemokine CCL5 / antagonists & inhibitors
  • Chemokine CCL5 / biosynthesis*
  • Chemokine CCL5 / genetics
  • Cloning, Molecular
  • Consensus Sequence
  • Endotoxins / administration & dosage
  • Endotoxins / immunology*
  • Histocytochemistry
  • Immune Tolerance* / genetics
  • In Vitro Techniques
  • Injections, Intraperitoneal
  • Kidney Glomerulus / chemistry
  • Kidney Glomerulus / immunology*
  • Kidney Glomerulus / metabolism*
  • Male
  • Molecular Sequence Data
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding / genetics
  • Protein Binding / immunology
  • Rats
  • Rats, Wistar
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*
  • Transcriptional Activation / immunology

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Chemokine CCL5
  • Endotoxins
  • NF-kappa B
  • Transcription Factor AP-1