The Role of Suppressor of Cytokine Signalling 3 in Regulating Toll like Receptor-mediated Intestinal Epithelial Homeostasis and Repair.

Thagia, Imtiyaz and Rigby, Rachael (2013) The Role of Suppressor of Cytokine Signalling 3 in Regulating Toll like Receptor-mediated Intestinal Epithelial Homeostasis and Repair. PhD thesis, Lancaster University.

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Abstract

The surface of the alimentary tract is lined with a single layer of intestinal epithelial cells (IEC) that functions as a barrier between commensal microflora and the underlying immune system. Maintenance of IEC barrier, subsequent to injury or physiological damage is essential in maintaining homeostasis. IECs express Toll-like receptors (TLR) on their surface which are able to detect microbial ligands such as helminth proteins, Poly I:C, lipopolysaccharide and flagellin, recognised by TLR2, TLR3, TLR4 and TLR5, respectively. Recent evidence proposes TLR-induced inflammatory pathways are vital for mucosal homeostasis with dysregulated repair predisposing individuals to inflammatory bowel disease (IBD). In IBD, the expression of suppressor of cytokine signalling -3 (SOCS3), a negative feedback inhibitor of inflammatory cytokines (TNFalpha, IL-6) is enhanced. The aim of this study was to investigate the role of SOCS3 on TLR-induced IEC responses associated with normal homeostasis and epithelial repair. SOCS3 over-expressing IEC were developed to assess its function on epithelial repair, gene and protein expression in response to microbial stimulation. Our results support previous data implicating TLR ligands being imperative for repair of damaged epithelial surfaces, and highlight a pivotal role of SOCS3 in mediating TLR-induced epithelial repair. Our results then go onto indicate over-expression of SOCS3 in IBD may perpetuate inflammation by promoting the production of pro-inflammatory TNFalpha in response to commensal microflora. In the final part of this study we show IEC become tolerant to commensal flora, protecting against incessant immune activation by commensals. In conclusion, these studies give credit to the hypothesis that SOCS3 influences microbial-induced IEC responses associated with normal homeostasis and epithelial repair. Furthermore, our data indicates SOCS3 expression must be tightly regulated permitting TLR-induced epithelial repair. The findings presented within this study offer a strong foundation for future in vivo studies on how SOCS3 impacts on intestinal disease.