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Title: The role of NF-κB regulation of eosinophil apoptosis and survival : implications for the pathogenesis of Hodgkin's disease
Author: Fujihara, Satoko
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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The role of NF-κB activation in the regulation of eosinophil survival and the potential contribution of apoptosis to the massive eosinophils presence found in Hodgkin’s disease was investigated. Activation of NF-κB is mediated by signal-induced phosphorylation via the IKK complex by TNF-α and degradation of its inhibitor, IκBα in the cytoplasm. Degradation of IκBα in the cytoplasm by TNF-α and translocation of NF-κB into the nucleus were determined by immunofluorescence and western blotting analysis. Various pharmacological reargents (e.g., the fungal metabolite gliotoxin and the proteaseome inhibitor Mg132) and the HIV-1-TAT transduction peptide linked with IκBα were used to stabilise and over-express IκBα in the cytoplasm resulting in the prevention of translocation of NF-κB into nucleus. The 11 amino acid TAT peptide linked with super-suppressive form of IκBα (IκBα32,36) was for the first time produced and transduced into eosinophils, HeLa and A549 cell lines, and resulted in an inhibition of NF-κB. Inhibition of TNF-α mediated IκBα degradation and prevented NF-κB regulated IL-8 production. It was notable however that the effect of TAT-IκBα32,36 was donor dependent. Hodgkin’s disease (or Hodgkin’s lymphoma) is characterised by a minority (about 1% of tumour mass) of neoplasic cells, the so called Hodgkin-Reed-Sternberg (HRS) cells, and where the ‘tumour’ mass is comprised of predominantly recruited eosinopihils. However, the mechanisms responsible for this eosinophil are currently unknown. In vitro, eosinophils cultured with supernatant derived from HRS cells caused a profound survival of eosinophils (e.g., supernatant treated eosinophils survived up to 6 times longer than non-treated eosinophils). This effect was blocked by various NF-κB inhibitors which caused eosinophil apoptosis, indicating the potential of NF-κB as a target for anti-tumour therapy in Hodgkin’s disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available