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Toll-like receptor 4-mediated nuclear factor kappa B activation is essential for sensing exogenous oxidants to

Rajendra Karki1, Orisa J Igwe

  • 1Division of Pharmacology and Toxicology, University of Missouri-Kansas City, Missouri, United States of America.

Plos One
|September 24, 2013
PubMed

Insights

Cells sense external oxidants and trigger inflammation via toll-like receptor 4 (TLR4) signaling. This pathway, involving NF-κB activation, contributes to chronic human diseases and inflammatory pain.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • The mechanisms by which cells detect external oxidants and initiate oxidative stress remain unclear.
  • Understanding these pathways is crucial for addressing inflammation in chronic human diseases.

Purpose of the Study:

  • To investigate how cells respond to exogenous oxidants and activate the NF-κB pathway.
  • To determine the role of toll-like receptors (TLRs), specifically TLR4, in mediating oxidant-induced inflammation.

Main Methods:

  • Utilized HEK-Blue cells engineered to express mouse TLR4 or TLR2 and an NF-κB-inducible SEAP reporter gene.
  • Challenged cells with receptor-specific ligands, pro-oxidants, and inhibitors; measured SEAP release as an indicator of NF-κB activation.
  • Administered a novel pro-oxidant in vivo to induce inflammatory responses in mice and assessed tissue markers.

Main Results:

  • Pro-oxidants significantly increased SEAP release in TLR4-expressing cells at lower concentrations than in TLR2-expressing cells.
  • TLR4-specific inhibitors and antioxidants attenuated oxidant-induced SEAP release, confirming TLR4 involvement.
  • In vivo studies showed that a novel pro-oxidant induced inflammatory pain and elevated TLR4, IL-1β, and TNFα levels, which were reduced by the antioxidant EUK-134.

Conclusions:

  • Exogenous oxidants primarily induce and sustain inflammation through a TLR4-dependent pathway.
  • This TLR4-mediated response to oxidants has significant implications for understanding and treating chronic inflammatory conditions.

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