gamma-Aminobutyric acid inhibits cytokine-mediated synergistic induction of astrocytic interleukin-6 release: A mechanistic study

A paucity of gamma-aminobutyric acid (GABA) levels is thought to encourage cytokine release in Alzheimer's disease (AD). A mechanistic investigation into the GABA-mediated suppression of the synergistic release of interleukin (IL)-6 by IL-1beta and tumor necrosis factor (TNF)-alpha is presented. Preliminary results indicate that p38 and nuclear factor (NF)-kappaB are essential for the synergistic release of IL-6 by IL-1beta and TNF-alpha. Both IL-1beta and TNF-alpha are able to stimulate the phosphorylation of p38, however, no synergistic stimulation was observed. IL-1beta or TNF-alpha is able to stimulate the degradation of the NF-kappaB inhibitor, IkappaB-alpha, with no change in IkappaB-beta. Interestingly, TNF-alpha is able to accelerate IkappaB-alpha degradation in the presence of IL-1beta. While GABA is unable to suppress IkappaB-alpha degradation and the phosphorylation of p38 by IL-1beta and TNF-alpha, it is postulated that GABA may be able to inhibit IL-6 concentrations by lessening the rate of IkappaB-alpha degradation.