mRNA and protein stability regulate the differential expression of pro- and anti-inflammatory genes in endotoxin-tolerant THP-1 cells

J Biol Chem. 2000 Apr 21;275(16):12185-93. doi: 10.1074/jbc.275.16.12185.

Abstract

The products of proinflammatory genes such as interleukin-1beta (IL-1beta) and cyclooxygenase-2 (COX-2) initiate many of the events associated with sepsis. Transcription of these genes is subsequently down-regulated, whereas expression of anti-inflammatory genes such as secretory interleukin-1 receptor antagonist (sIL-1 RA) is maintained. Differential expression is associated with endotoxin tolerance, a cellular phenomenon common to sepsis and characterized by reduced proinflammatory gene expression after repeated exposure to lipopolysaccharide. As a model for endotoxin tolerance, we examined the expression of COX-2 and sIL-1 RA in a human promonocyte cell line, THP-1. We observed a 5-fold decrease in COX-2 protein in endotoxin-tolerant cells relative to control cells. In contrast, sIL-1 RA protein increased 5-fold in control and tolerant cells and remained elevated. Decreased COX-2 production is due to repressed transcription and not enhanced mRNA degradation. In addition, COX-2 protein is turned over rapidly. Transcription of sIL-1 RA is also repressed during tolerance. However, sIL-1 RA mRNA is degraded more slowly than COX-2 mRNA, allowing continued synthesis of sIL-1 RA protein that is very stable. These results indicate that differential expression during endotoxin tolerance occurs by transcriptional repression of COX-2 and by protein and mRNA stabilization of sIL-1 RA.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line
  • Cyclooxygenase 2
  • Down-Regulation
  • Drug Tolerance
  • Humans
  • Inflammation / genetics*
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Lipopolysaccharides / pharmacology*
  • Membrane Proteins
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Proteins / metabolism*
  • RNA, Messenger / metabolism*
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sialoglycoproteins / genetics
  • Sialoglycoproteins / metabolism
  • Transcription, Genetic / drug effects

Substances

  • IL1RN protein, human
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Isoenzymes
  • Lipopolysaccharides
  • Membrane Proteins
  • Proteins
  • RNA, Messenger
  • Receptors, Interleukin-1
  • Recombinant Proteins
  • Sialoglycoproteins
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases