Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets

FASEB J. 2002 Dec;16(14):1861-8. doi: 10.1096/fj.02-0503com.

Abstract

The peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor whose activation regulates metabolism and inflammation. Recent data indicate that the zinc finger transcription factor early growth response gene-1 (Egr-1) acts as a master switch for the inflammatory response in ischemic vessels. Experiments tested the hypothesis that activation of endogenous PPAR-gamma inhibits induction of Egr-1. Egr-1 is rapidly induced in murine lungs after ischemia-reperfusion, as well as in alveolar mononuclear phagocytes deprived of oxygen as an ischemic model. In vitro, the natural PPAR-gamma ligand (15-deoxy-Delta12,14-prostaglandin J2) and a PPAR-gamma activator (troglitazone), but not a PPAR-alpha activator (bezafibrate), strikingly diminished Egr-1 mRNA and protein expression and nuclear DNA binding activity corresponding to Egr-1. In vivo, treatment with troglitazone before ischemia prevented induction of Egr-1 and its target genes such as interleukin-1beta, monocyte chemotactic protein-1, and macrophage inflammatory protein-2. As a consequence of PPAR-gamma activation, pulmonary leukostasis was decreased and oxygenation and overall survival were improved. Activation of PPAR-gamma suppresses activation of Egr-1 and its inflammatory gene targets and provides potent protection against ischemic pulmonary injury. These data reveal a new mechanism whereby PPAR-gamma activation may decrease tissue inflammation in response to an ischemic insult.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cell Movement / drug effects
  • Chromans / pharmacology
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics
  • Early Growth Response Protein 1
  • Gene Expression Regulation
  • Immediate-Early Proteins*
  • Inflammation / immunology
  • Leukocytes / drug effects
  • Leukocytes / immunology
  • Ligands
  • Lung / drug effects
  • Lung / immunology
  • Lung / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phagocytes / metabolism
  • RNA, Messenger / biosynthesis
  • Rats
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Reperfusion Injury / genetics
  • Reperfusion Injury / immunology*
  • Reperfusion Injury / metabolism
  • Survival Analysis
  • Thiazoles / pharmacology
  • Thiazolidinediones*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Troglitazone

Substances

  • Chromans
  • Cytokines
  • DNA-Binding Proteins
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Egr1 protein, rat
  • Immediate-Early Proteins
  • Ligands
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Troglitazone