Characterisation of the role of Fas in intestinal inflammation and cancer

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dc.contributor.advisor Houston, Aileen M. en
dc.contributor.advisor Brint, Elizabeth K. en Fernandes, Philana 2015-11-24T12:09:22Z 2015 2015
dc.identifier.citation Fernandes, P. 2015. Characterisation of the role of Fas in intestinal inflammation and cancer. PhD Thesis, University College Cork. en
dc.identifier.endpage 212
dc.description.abstract Background: The role of Fas (CD95) and its ligand, Fas ligand (FasL/CD95L), is poorly understood in the intestine. Whilst Fas is best studies in terms of its function in apoptosis, recent studies suggest that Fas ligation may mediate additional, non-apoptotic functions such as inflammation. Toll like Receptors (TLRs) play an important role in mediating inflammation and homeostasis in the intestine. Recent studies have shown that a level of crosstalk exists between the Fas and TLR signalling pathways but this has not yet been investigated in the intestine. Aim: The aim of this study was to evaluate potential cross-talk between TLRs and Fas/FasL system in intestinal cancer cells. Results: Treatment with TLR4 and TLR5 ligands, but not ligands for TLR2 and TLR9 increased the expression of Fas and FasL in intestinal cancer cells in vitro. Consistent with this, expression of Fas and FasL was reduced in the distal colon tissue from germ-free (GF), TLR4 and TLR5 knock-out (KO) mice but was unchanged in TLR2KO tissue, suggesting that intestinal cancer cells display a degree of specificity in their ability to upregulate Fas and FasL expression in response to TLR ligation. Expression of both Fas and FasL was significantly reduced in TRIF KO tissue, indicating that signalling via TRIF by TLR4 and TLR5 agonists may be responsible for the induction of Fas and FasL expression in intestinal cancer cells. In addition, modulating Fas signalling using agonistic anti-Fas augmented TLR4 and TLR5-mediated tumour necrosis factor alpha (TNFα) and interleukin 8 (IL)-8 production by intestinal cancer cells, suggesting crosstalk occurs between these receptors in these cells. Furthermore, suppression of Fas in intestinal cancer cells reduced the ability of the intestinal pathogens, Salmonella typhimurium and Listeria monocytogenes to induce the expression of IL-8, suggesting that Fas signalling may play a role in intestinal host defence against pathogens. Inflammation is known to be important in colon tumourigenesis and Fas signalling on intestinal cancer cells has been shown to result in the production of inflammatory mediators. Fas-mediated signalling may therefore play a role in colon cancer development. Suppression of tumour-derived Fas by 85% led to a reduction in the tumour volume and changes in tumour infiltrating macrophages and neutrophils. TLR4 signalling has been shown to play a role in colon cancer via the recruitment and activation of alternatively activated immune cells. Given the crosstalk seen between Fas and TLR4 signalling in intestinal cancer cells in vitro, suppressing Fas signalling may enhance the efficacy of TLR4 antagonism in vivo. TLR4 antagonism resulted in smaller tumours with fewer infiltrating neutrophils. Whilst Fas downregulation did not significantly augment the ability of TLR4 antagonism to reduce the final tumour volume, Fas suppression may augment the anti-tumour effects of TLR4 antagonism as neutrophil infiltration was further reduced upon combinatorial treatment. Conclusion: Together, this study demonstrates evidence of a new role for Fas in the intestinal immune response and that manipulating Fas signalling has potential anti-tumour benefit. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2015, Philana Fernandes. en
dc.rights.uri en
dc.subject Fas en
dc.subject CD95 en
dc.subject TLR en
dc.subject Inflammation en
dc.subject Cancer en
dc.subject Colon en
dc.title Characterisation of the role of Fas in intestinal inflammation and cancer en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text available en Please note that Chapter 5 (pp.123-175) is unavailable due to a restriction requested by the author. en 10000-01-01
dc.description.version Accepted Version
dc.contributor.funder Science Foundation Ireland en
dc.description.status Not peer reviewed en Medicine en Pathology en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.chapterOfThesis Chapter 5
dc.check.embargoformat Both hard copy thesis and e-thesis en
dc.internal.conferring Summer Conferring 2015

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