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Title: TNF signalling in endothelial cells
Author: Zhou, Zhigang.
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2007
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Pleiotropic cytokine tumour necrosis factor a (TNF) is the archetypal member of a large super-family of ligands and associated receptors. Through its two surface presenting receptors, TNFRI and TNFR2, TNF can elicit responses such as differentiation, proliferation, and apoptosis, depending on several factors such as microenvironment, cell cycle, and cell type. Recent evidence indicated that TNF can be up-regulated in endothelial cells (EC) upon their stimulation and plays an important role in regulating EC responses which have been implicated in several cardiovascular diseases, such as heart failure and atherosclerosis. Anti-TNF therapy has been successfully applied on several inflammatory related diseases, such as rheumatoid arthritis and Crohn's disease. Conversely, for heart failure patients, anti-TNF therapy has been considered but has been disappointing in trials thus far. Therefore, a greater understanding of TNF's ability to signal disparate responses is essential for the development of more effective TNF- or signalling-based therapeutics. Here we demonstrate that the regulation of TNF activity in endothelial cells is controlled by two distinct receptor signalling pathways via its associated adaptor and downstream effector proteins, cross-linked by potential crosstalk mechanisms at different cascades. Our findings clearly demonstrate that TNF activates both the canonical and non-canonical NF-KB pathways, mainly through TNFRI signalling while TNFR2-driven NF-KB nuclear translocation is mainly inhibitory. TNF regulated NF-KB dependent genes including adhesion molecules which were up-regulated via the TNFRI receptor pathway; MAPKs activation may interact with TNF-driven signal at several cascades for fine tuning of its overall effects. We also discovered that TNFR2 is able to switch on survival signals via induction of the protective genes heme oxygenase-1 (HO-1) and ferritin or through the auto-regulation of TNFR2 itself. Through our findings, we hypothesised that TNF elicits in EC its pro-inflammatory effects mainly through TNFRI while balancing the overall signalling response by the survival signals mediated via TNFR2. Our results have implications for improving anti-TNF therapeutic strategies by selective inhibition of TNF receptor signalling rather than inhibiting TNF as a whole.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available