UBC Theses and Dissertations
The role of endoplasmic reticulum stress and inflammasome activation in inflammatory disease : identifying therapeutic targets in cystic fibrosis and haematological malignancies Tang, Anthony Chi-Hai
An increasing number of infectious and inflammatory conditions have identified ER stress and IL-1β as central driving forces in inflammation. In the following studies, we have identified several important pathways that promote the cycle of pulmonary inflammation in cystic fibrosis (CF), including the IL-1β regulation by NF-κB, IL-1β stimulation of neutrophil chemokine production by airway epithelial cells, and inhibition of neutrophil chemokine secretion through ER stress signaling. Based on our observations, we conclude that CF environmental factors such as increased NF-κB priming by chronic infection and the presence of ER stressors can significantly augment inflammatory responses by controlling the maturation of IL-1β. These effects appear to be cell type and cytokine-specific, as downstream induction of CXCL1 and IL-8, key neutrophil chemokines that we found were associated with lung disease severity in CF patients, can also be suppressed by ER stress-mediated inhibition of STAT3 signaling in airway epithelial cells. Interestingly, we also found that by varying the time of TLR stimulation relative to the induction of ER stress (particularly by proteasome inhibition), we could obtain differential effects on IL-1β production and maturation. We reasoned that these effects could be important in haematological malignancies where proteasome inhibition has recently become a successful first-line treatment. Not only was tumour cell cytotoxicity significantly increased by addition of a TLR adjuvant, IL-1β production could be controlled depending on when the adjuvant was added relative to the proteasome inhibitor. This could be a useful method in which IL-1β-mediated responses can be manipulated while also increasing tumour cell death.
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