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Published on: December 30, 2016

Oxidants selectively reverse TGF-beta suppression of proinflammatory mediator production

Yi Qun Xiao1, Celio G Freire-de-Lima, William J Janssen

  • 1Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|January 6, 2006
PubMed

Insights

Oxidative stress, like hydrogen peroxide, can block TGF-beta

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Transforming growth factor-beta (TGF-beta) typically inhibits inflammatory mediators.
  • However, its anti-inflammatory effects may fail in severe acute inflammation.
  • Oxidative stress is implicated as a potential disruptor of TGF-beta signaling.

Purpose of the Study:

  • To investigate the role of oxidative stress in modulating TGF-beta's anti-inflammatory functions.
  • To determine how oxidative stress affects TGF-beta signaling pathways, specifically NF-kappaB and Smad pathways.

Main Methods:

  • Stimulation of RAW 264.7 macrophage cells and primary human/mouse alveolar macrophages with lipopolysaccharide (LPS).
  • Treatment with TGF-beta and hydrogen peroxide (H2O2) to assess effects on inflammatory mediator production.
  • Analysis of key signaling molecules including p38 MAPK, ERK, MAPK phosphatase-1, Src tyrosine kinases, protein phosphatase-1/2A, and Smad2 phosphorylation.

Main Results:

  • TGF-beta inhibited LPS-induced pro-inflammatory mediator production.
  • Hydrogen peroxide prevented TGF-beta's inhibitory effect on pro-inflammatory mediators.
  • H2O2-induced p38 MAPK activation blocked TGF-beta's induction of ERK activation and MAPK phosphatase-1, mediated by Src and PP1/2A.
  • TGF-beta-induced Smad2 phosphorylation and reporter gene transcription remained unaffected by H2O2.

Conclusions:

  • Oxidative stress disrupts the anti-inflammatory actions of TGF-beta by interfering with specific signaling pathways.
  • TGF-beta's effects on cellular differentiation and matrix production, mediated by Smad signaling, are preserved under oxidative stress.
  • This suggests a mechanism by which oxidative stress compromises TGF-beta's ability to resolve inflammation.

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