| Summary: | 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. <i>In vitro,</i> 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.
|
|---|
