Regulation of interleukin-6 gene expression in brain of aged mice by nuclear factor kappaB.

Interleukin-6 (IL-6) is increased in brain of aged mice. The purpose of this study was to determine if binding of nuclear factor kappaB (NFkappaB) to the IL-6 promoter is responsible for the age-related increase in brain IL-6. In an initial study, the effect of age on IL-6 in brain was verified as IL-6 protein was increased in brain of aged mice compared to adult and juvenile mice. Competitive RT-PCR showed that IL-6 mRNA concentration was at least 4-fold higher in aged brain compared to adult brain. Next, binding of the transcription factor NFkappaB to the IL-6 promoter in brains of 1-, 6-, and 24-month-old mice was determined. Electrophoretic mobility shift assay showed that NFkappaB activity was increased in aged brain compared to adult and juvenile brain. Moreover, glial cells cultured from aged mice showed more NFkappaB DNA-binding activity and more IL-6 mRNA and protein expression than glia from adults. However, incubating glia from aged mice in the presence of kappaB decoy inhibited these effects of age. The same was observed in vivo as intracerebroventricular injection of kappaB decoy in aged mice decreased NFkappaB activity and IL-6 mRNA and protein in brain. These results show that the DNA-binding activity of NFkappaB is increased in the brain of aged mice and that at least one consequence is increased expression of IL-6.