Nrf2-dependent Protection From LPS Induced Inflammatory Response and Mortality by CDDO-Imidazolide

Biochem Biophys Res Commun. 2006 Dec 29;351(4):883-9. doi: 10.1016/j.bbrc.2006.10.102. Epub 2006 Oct 30.

Abstract

Sepsis induced lethality is characterized by amplified host innate immune response. Nrf2, a bZIP transcription factor, regulates a battery of cellular antioxidative genes and maintains cellular redox homeostasis. This study demonstrates that increasing Nrf2 activity by a potent small molecule activator, CDDO-Im (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole), protects from deregulation of lipopolysaccharide (LPS) induced innate immune response. In response to LPS stimuli, nrf2-deficient (nrf2 -/-) peritoneal neutrophils showed increased NADPH oxidase-dependent ROS generation, proinflammatory cytokines (Tnf-alpha and Il-6) and chemokines (Mip2 and Mcp-1) relative to wild-type (nrf2 +/+) cells. Pretreatment of peritoneal neutrophils with CDDO-Im induced antioxidative genes (Ho-1, Gclc, Gclm, and Nqo1) and attenuated LPS induced ROS generation as well as expression of proinflammatory cytokines exclusively in nrf2 +/+ neutrophils but not in nrf2 -/- cells. In corroboration with in vitro studies, pretreatment with CDDO-Im induced Nrf2-dependent antioxidative genes, attenuated LPS induced proinflammatory cytokine expression, and decreased mortality specifically in the nrf2 +/+ mice. In conclusion, the results suggest that Nrf2 is associated with oxidative regulation of LPS induced innate immune response in neutrophils. Activation of Nrf2-dependent compensatory antioxidative pathways by CDDO-Im protects from LPS induced inflammatory response and mortality.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chemokines / metabolism*
  • Cytokines / metabolism*
  • Gene Expression / drug effects
  • Imidazoles / toxicity
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / immunology
  • Lipopolysaccharides / toxicity
  • Lung / drug effects
  • Lung / immunology
  • Mice
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / physiology*
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Oleanolic Acid / analogs & derivatives
  • Oleanolic Acid / toxicity
  • Oxidative Stress*
  • Reactive Oxygen Species / metabolism

Substances

  • 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
  • Chemokines
  • Cytokines
  • Imidazoles
  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Reactive Oxygen Species
  • Oleanolic Acid