Nox2-derived ROS in PPARγ signaling and cell-cycle progression of lung alveolar epithelial cells

Free Radic Biol Med. 2011 Aug 1;51(3):763-72. doi: 10.1016/j.freeradbiomed.2011.05.027. Epub 2011 May 30.

Abstract

Reactive oxygen species (ROS) play important roles in peroxisome proliferator-activated receptor γ (PPARγ) signaling and cell-cycle regulation. However, the PPARγ redox-signaling pathways in lung alveolar epithelial cells remain unclear. In this study, we investigated the in vivo and in vitro effects of PPARγ activation on the levels of lung ROS production and cell-cycle progression using C57BL/6J wild-type and Nox2 knockout mice (n=10) after intraperitoneal injection of a selective PPARγ agonist (GW1929, 5 mg/kg body wt, daily) for 14 days. Compared to vehicle-treated mice, GW1929 increased significantly the levels of ROS production in wild-type lungs, and this was accompanied by significant up-regulation of PPARγ, Nox2, PCNA, and cyclin D1 and phosphorylation of ERK1/2 and p38MAPK. These effects were absent in Nox2 knockout mice. In cultured alveolar epithelial cells, GW1929 (5 μM for 24 h) increased ROS production and promoted cell-cycle progression from G0/G1 into S and G2/M phases, and these effects were abolished by (1) adding a PPARγ antagonist (BADGE, 1 μM), (2) knockdown of PPARγ using siRNA, or (3) knockout of Nox2. In conclusion, PPARγ activation through Nox2-derived ROS promotes cell-cycle progression in normal mouse lungs and in cultured normal alveolar epithelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzophenones / administration & dosage
  • Benzophenones / adverse effects
  • Cell Cycle / drug effects*
  • Cell Line
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NADPH Oxidase 2
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Oxidative Stress / drug effects
  • PPAR gamma / agonists
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Pulmonary Alveoli / drug effects*
  • Pulmonary Alveoli / metabolism
  • Pulmonary Alveoli / pathology
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species / metabolism
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tyrosine / administration & dosage
  • Tyrosine / adverse effects
  • Tyrosine / analogs & derivatives

Substances

  • Benzophenones
  • Membrane Glycoproteins
  • PPAR gamma
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Tyrosine
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • GW 1929