The effect of age on cyclooxygenase-2 gene expression: NF-kappaB activation and IkappaBalpha degradation.
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.
Kim
H J
HJ
College of Pharmacy, Pusan, South Korea.
Kim
K W
KW
Yu
B P
BP
Chung
H Y
HY
D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001483:Base Sequence; D051546:Cyclooxygenase 2; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D020672:I-kappa B Proteins; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D018384:Oxidative Stress; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D051996:Transcription Factor RelA; D015533:Transcriptional Activation
D000906:Antibodies; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005609:Free Radicals; D020672:I-kappa B Proteins; D007527:Isoenzymes; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases