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Title: Regulation of granulocyte apoptosis by glucocorticoids and cyclic AMP
Author: Martin, M. C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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Investigations were undertaken to examine the cyclic AMP signal transduction pathway responsible for delay of neutrophil apoptosis. Despite increasing protein kinase A (PKA) activity, this kinase is unlikely to mediate the effects of cyclic AMP in apoptosis since blockade of PKA activation did not influence the survival effects of cyclic AMP. Furthermore cyclic AMP mediated delay of neutrophil apoptosis is independent of PI-3 kinase and MAP kinase activation. Our results suggest cyclic AMP delays neutrophil apoptosis via a novel, reversible and transcriptionally independent mechanism. We show that proteasome activity in the neutrophil is vitally involved in this process and suggest that a balance of pro-apoptotic and anti-apoptotic proteins play a key role in the powerful ability of cyclic AMP to delay neutrophil death. Additional studies were aimed to elucidating the underlying mechanisms of glucocorticoid regulation of granulocyte apoptosis. Glucocorticoids were found to exert diametrically opposed effects on eosinophils and neutrophils, causing induction of apoptosis in eosinophils while delaying neutrophil cell death. Granulocytes were found to express the glucocorticoid receptor (GR) however the nature of isoforms expressed remains undefined. Glucocorticoid regulation of apoptosis in both cell types was found to require hsp90 activity. The use of pharmacological inhibitors suggested that histone deacetylation was not involved in either glucocorticoid inhibition of neutrophil apoptosis or glucocorticoid induction of eosinophil cell death but may be implicated in regulation of constitutive granulocyte apoptosis. In summary, there is good evidence implicating glucocorticoids and cyclic AMP in the regulation of granulocyte apoptosis. A greater understanding of the signalling mechanisms by which these mediators regulate granulocyte death could potentially lead to the development of novel strategies to therapeutically induce apoptosis for the resolution of inflammation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available