| dc.description.abstract | Inflammation is the cornerstone of homeostasis. At one end of the spectrum,
inflammation is activated by severe disturbances to homeostasis, typically as a
result of infection or injury. Inflammation in this context is acute and identifiable by
the five cardinal signs of inflammation- rubor, calor, tumor, dolor and functio laesa.
Inflammation in response to infection and injury is well characterized and we now
have a detailed understanding of the molecules, PAMPs and DAMPs, that promote
inflammation in these contexts. However, at the other end spectrum, inflammation
can also be initiated in response to deviations from homeostatic set points, typically
induced by cell stress. Inflammation in this context is typically of a lower magnitude
and not as apparent as PAMP/DAMP-initiated inflammation. If unresolved, cell
stress-induced inflammation can become chronic and contribute to the
pathogenesis of major health conditions including cancer, diabetes and
neurodegenerative disease. While the molecular mechanism of PAMP- and DAMP-
induced inflammation is well characterized, the key sensors and signalling
molecules involved in cell stress-induced inflammation remain to be elucidated. This
thesis aims to explore the molecular pathways mediating inflammation in response
to proteotoxic stress.
Chapter three of this thesis demonstrates that proteasome inhibition is a potent
initiator of inflammation. We demonstrate that, in the absence of PAMPs or DAMPs,
clinically approved proteasome inhibitors, bortezomib and carfilzomib, triggered the
release of a number of inflammatory cytokines and chemokines in multiple cell lines.
We also show that proteasome inhibitors induce NF-kB activation, and inflammation
in this context was dependent on the p65 subunit of NF-kB as well as the upstream
kinase TAK1.
Chapter four of this thesis investigates the stress response pathway mediating NF-
kB activation upon proteasome inhibition. Surprisingly, we identify the oxidative
stress-inducible transcription factor, NRF2, as a key regulator of proteasome
inhibition-induced IL-8 synthesis and secretion. Additionally, we also demonstrate a
role for the KEAP1/NRF2 pathway in TNFa- and IL-1a-initiated inflammatory
signalling, suggesting that NRF2 positively regulates inflammation in a number of
important inflammatory pathways.
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Finally, in chapter five, we investigate the molecular basis of NRF2-induced
inflammation and partly elucidate the molecular mechanism involved. We
demonstrate that NRF2-induced inflammation is dependent on the NF-kB subunit
p65 and that these transcription factors appear to act cooperatively and
synergistically. With preliminary results, we observed an interaction between NRF2
and p65, suggesting that these molecules may promote transcription as part of a
shared complex. Therefore, NRF2 can serve as an enhancer of NF-kB-driven
inflammation in a number of contexts, possibly through direct interactions between
the p65 subunit of NF-kB and NRF2. | en |
