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Title: Mechanisms regulating granulocyte apoptosis
Author: Ward, Carol
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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Few factors present at inflammatory foci have not been demonstrated to accelerate granulocyte apoptosis; most inhibit the process, adding to the longevity of these cells. The purpose of these studies was to examine the role of different classes of inflammatory mediators in the induction of granulocyte apoptosis and investigate the possible mechanisms involved. We have shown that the majority of pro-inflammatory cytokines inhibit the process of apoptosis in granulocytes. The anti-inflammatory cytokine IL-10 had no effect on granulocyte apoptosis, but in neutrophils, it inhibited the survival effects of LPS. TGF-β, inhibited granulocyte apoptosis but potentiated the pro-apoptotic effects of TNF-α, at early timepoints in neutrophils. Eicosanoids also exert differential effects on granulocyte apoptosis, however prostaglandins of the J series proved to be potent inducers of apoptosis in both cell types. The use of receptor agonists demonstrated that these pro-apoptosis effects may be mediated via a class of intracellular peroxisome proliferator activated receptors (PPARs), for which these prostanoids are ligands. Both TGF-β and PPARs can inhibit the transcription factor nuclear factor-kappa B (NF-κB). Further examination of the role of this transcription factor in granulocyte apoptosis illustrated that it exerts potent survival effects in both neutrophils and eosinophils, and that inhibition of its activation synergistically enhanced the pro-apoptotic response of TNF-α in neutrophils, and induced eosinophils to respond to the pro-apoptotic effects of this cytokine. The data presented strongly support the hypothesis that NF-κB activation is necessary for the survival of granulocytes, and that certain physiological mediators, such as TNF-α, prostaglandins of the J series and the cytokine TGF-β may be involved in the physiological resolution of inflammation, by inhibiting the activity of this transcription factor.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available