Involvement of reactive oxygen species in cyclic stretch-induced NF-κB activation in human fibroblast cells

Hideki Amma, Keiji Naruse, Naoki Ishiguro, Masahiro Sokabe

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50 Citations (Scopus)


Uniaxial cyclic Stretch leads to an upregulation of cyclooxygenase (COX)-2 through increases in the intracellular Ca 2+ concentration via the stretch-activated (SA) channel and following nuclear factor kappa B (NF-κB) activation in human fibroblasts. However, the signaling mechanism as to how the elevated Ca 2+ activates NF-κB is unknown. In this study, we examined the involvement of reactive oxygen species (ROS) as an intermediate signal, which links the elevated Ca 2+ with NF-κB activation. 4-Hydroxy-2-nonenal (HNE) was produced and modified IκB peaking at 2 min. The phosphorylation of IκB peaked at 8 min. HNE modification and IκB phosphorylation, NF-κB translocation to the nucleus, and following COX-2 production were inhibited by extracellular Ca 2+ removal or Gd 3+ application, as well as by the antioxidants. The stretch-induced Ca 2+ increase was inhibited by extracellular Ca 2+ removal, or Gd 3+ application. IκB kinase (IKK) activity peaked at 4 min, which was inhibited by extracellular Ca 2+ removal, Gd 3+ or the antioxidants. IKK was also HNE-modified and, similarly to IκB, peaked at 2 min. IKK under static conditions was activated by exogenously applied HNE at a relatively low dose (1 μM), while it was inhibited at higher concentrations, suggesting that HNE could be one of the candidate signals in the stretch-induced NF-κB activation. The present study suggests that the NF-κB activation by cyclic stretch is mediated by the following signal cascade: SA channel activation → intracellular Ca 2+ increase → production of ROS → activation of IKK → phosphorylation of IκB → NF-κB translocation to the nucleus.

Original languageEnglish
Pages (from-to)364-373
Number of pages10
JournalBritish Journal of Pharmacology
Issue number3
Publication statusPublished - Jun 2005
Externally publishedYes


  • 4-hydroxy-2-nonenal
  • Antioxidants
  • Calcium
  • Cyclic stretch
  • Fibroblast
  • IκB kinase
  • NF-κB
  • Reactive oxygen species

ASJC Scopus subject areas

  • Pharmacology


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