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

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.