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.