Award Date

1-1-2007

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Committee Member

Bryan L. Spangelo

Number of Pages

67

Abstract

A decline in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may enhance cytokine release in Alzheimer's disease (AD) resulting in neuroinflammation. We investigated the GABA-mediated suppression of the synergistic release of interleukin-6 (IL-6) due to interleukin 1-beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) synergy. Our results indicate that p38 and nuclear factor (NF)-kappaB are essential for the synergistic release of IL-6 by IL-1beta and TNFalpha. Both IL-1beta and TNF-alpha stimulate p38 phosphorylation and each are able to enhance the degradation of the NF-kappaB inhibitor, IkappaB-alpha, with no change in IkappaB-beta. Interestingly, co-treatments IL-1beta and TNF-alpha induce a greater increase in IkappaB-alpha degradation compared to either cytokine alone. In addition, co-treatment increased IL-6 mRNA indicating synergy on a transcriptional level. In addition, Western blot analysis revealed that co-treatments of IL-1beta and TNF-alpha resulted in an increase of IL-6 protein that can be reversed by GABA. Furthermore, co-treatments of IL-1beta and TNF-alpha resulted in activation of p38 and degradation of IkappaB-alpha at earlier time points compared to either cytokine alone. These data suggests that IL-1beta and TNF-alpha synergizes by accelerating p38 and NF-kappaB activation, increasing IL-6 transcription. Although GABA suppressed the IL-1beta and TNF-alpha synergistic release of IL-6, it did not affect IkappaB-alpha or IkappaB-beta degradation, p38 phosphorylation or IL-6 transcription. Instead it appears that GABA may inhibit IL-6 translation. We have demonstrated that this synergistic release of IL-6 can be inhibited by GABA and its receptor agonists.

Keywords

Acid; Activation; Aminobutyric; Astrocytoma; Cells; Gamma; Inhibits; Interleukin Release; Synergistic; Transcriptional

Controlled Subject

Biochemistry; Neurosciences

File Format

pdf

File Size

1.27 MB

Degree Grantor

University of Nevada, Las Vegas

Language

English

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