Award Date

1-1-2008

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Committee Member

Bryan L. Spangelo

Number of Pages

77

Abstract

Astrocytes respond to pro-inflammatory cytokines such as, interleukin-1 (IL-1beta) and tumor necrosis factor (TNF-alpha). However, the mechanisms in which IL-1beta and TNF-alpha mediate cell's signaling need further investigation; In previous research, the effects of y-aminobutyric acid (GABA) on IL-1 and TNF-alpha signaling pathway were studied. GABA was unable to suppress IkappaB-alpha degradation and the phosphorylation of p38 by IL-1beta and TNF-alpha. However, it was suggested that GABA may be able to inhibit IL-6 release by reducing the rate of IkappaB-alpha degradation; Another cytokine, IL-10, which is well known in literature to have anti-inflammatory effects, is investigated in this study. This study presents IL-10 effects on the NF-kappaB and p38 signaling pathways as well as IL-10 inhibition of IL-1 and TNF synergistic induction of IL-6 release. The effect of other signaling molecules, believed to act as antagonists for p38 activation, were also investigated and presented in this study. Previous studies indicate that both IL-1beta and TNF-alpha were able to stimulate the phosphorylation of p38 and the degradation of NF-kappaB inhibitor, IkappaB-alpha, with no change in IkappaB-beta. While IL-10 is unable to suppress the phosphorylation of p38 by IL-1beta or TNF-alpha or degradation of IkappaB-alpha, inhibitor of NF-kappaB, it is also suggested that IL-10 may inhibit cytokine-mediated synergistic induction of IL-6 in mechanistically similar way to GABA; Inflammatory cytokines IL-1beta and TNF-alpha have repeatedly shown to phosphorylate p38 and activate NF-kappaB pathway. We also have shown their synergistic effect on release of extracellular IL-6 as well as synergistic increase in transcriptional activation of IL-6 mRNA. Anti-inflammatory effects of IL-10, GABA and p38 inhibitor SB203580 were also investigated. Experimental results suggest that neither IL-10 nor GABA can reverse p38 or NF-kappaB activation induced by IL-1beta and TNF-alpha. However, they inhibit synergistic release of IL-6 but have no effect on IL-6 transcriptional activation. Further, SB203580, inhibitor of p38, decreased synergistic mRNA transcript after stimulation with IL-1beta and TNF-alpha. Our findings may postulate that anti-inflammatory molecules such as GABA and IL-10 may have similar mode of action supposedly affecting post-translational mechanisms.

Keywords

Astrocytoma; Cells; Cytokine; Inhibits; Interleukin; Mediated; Release; Synergistic

Controlled Subject

Biochemistry; Cellular biology

File Format

pdf

File Size

1.35 MB

Degree Grantor

University of Nevada, Las Vegas

Language

English

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