Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide

Rajesh K. Thimmulappa, Catherine Scollick, Kassim Traore, Melinda Yates, Michael A. Trush, Karen T. Liby, Michael B. Sporn, Masayuki Yamamoto, Thomas W. Kensler, Shyam Biswal

Research output: Contribution to journalArticlepeer-review

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-α 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.

Original languageEnglish (US)
Pages (from-to)883-889
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume351
Issue number4
DOIs
StatePublished - Dec 29 2006

Keywords

  • Antioxidant
  • CDDO-Im
  • Innate immune response
  • Macrophages
  • Neutrophils
  • Nrf2
  • ROS

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide'. Together they form a unique fingerprint.

Cite this