The effect of age on cyclooxygenase-2 gene expression: NF-kappaB activation and IkappaBalpha degradation

Free Radic Biol Med. 2000 Mar 1;28(5):683-92. doi: 10.1016/s0891-5849(99)00274-9.

Abstract

Increased oxidative stress resulting in the activation of NF-kappaB is thought to play a crucial role in the expression of the cyclooxygenase-2 (COX-2), which is the key enzyme in proinflammatory prostanoid synthesis. In the current study, we investigated whether the aging process affects the status of the redox-sensitive NF-kappaB in rat kidney, and how this age-related modulation is related to COX-2 gene expression and COX-derived reactive oxygen species (ROS). We found that the aging process strongly enhanced the activation of NF-kappaB and its DNA-binding activity with an increased ROS status. Accompanied with the change in the NF-kappaB activity was a decreased IkappaBalpha as confirmed by the increased nuclear p65 protein. Thus, these data strongly indicated that the aging process increases NF-kappaB activity by downregulating IkappaBalpha. A closer examination further revealed that age-related oxidative status correlated with the increased COX-derived prostanoid biosynthetic process is mediated by the increased NF-kappaB-regulated COX activity. This increase in NF-kappaB activity was accompanied by the increased COX-2 mRNA and protein levels. Based on these data, we concluded that the age-related increase in redox-sensitive NF-kappaB translocation and binding activities are associated with increased ROS, and further that this transactivation was modulated by the age-related decrease of IkappaBalpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Aging / metabolism*
  • Animals
  • Antibodies / pharmacology
  • Base Sequence
  • Cyclooxygenase 2
  • DNA Primers / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Free Radicals / metabolism
  • Gene Expression Regulation, Enzymologic
  • I-kappa B Proteins*
  • Isoenzymes / genetics*
  • Isoenzymes / metabolism
  • Kidney / metabolism
  • Male
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • NF-kappa B p50 Subunit
  • Oxidative Stress
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred F344
  • Reactive Oxygen Species / metabolism
  • Transcription Factor RelA
  • Transcriptional Activation

Substances

  • Antibodies
  • DNA Primers
  • DNA-Binding Proteins
  • Free Radicals
  • I-kappa B Proteins
  • Isoenzymes
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Nfkbia protein, rat
  • RNA, Messenger
  • Reactive Oxygen Species
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases