Smith, Emily and Rigby, Rachael and Broughton, Susan (2016) The conservation of suppressor of Cytokine Signalling 3 in mediating intestinal homeostasis. PhD thesis, Lancaster University.
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Abstract
A key function of the gastrointestinal tract is to break down ingested food and absorb the contained nutrients and water. Within the intestinal tract are a number of specialised epithelial cells that aid in this process as well as maintaining immune homeostasis through their functioning as a physical barrier, and secretion of antimicrobial peptides. The intestinal tract has one of the highest turnover rates within organisms, so because of this, and the variety of functions these cells can carry out, it is essential that the balance of proliferation and cell death is regulated to maintain homeostasis. There are several conserved signalling pathways that are responsible for the proliferation of intestinal cells. Suppressor of cytokine signalling 3 (SOCS3) is produced upon activation of the Janus kinase/Signal transducer and activator of transcription (Jak/Stat) pathway and this is an inducer of negative feedback inhibition and is implicated in regulation of intestinal homeostasis, with SOCS3 dysregulation reported in intestinal pathologies, such as cancer and inflammatory bowel disease. Intestinal epithelial cells are also in close proximity to the commensal gut microbiota and they too are known to regulate intestinal turnover. In the work presented here, we assessed the role of SOCS3 in normal intestinal homeostasis and how microbe-mediated proliferation impacts upon this. These experiments were performed in three different biological models, allowing us to assess the impact of SOCS3-regulated homeostasis at the molecular level, the tissue level, and at an organismal level, and also determine whether the function of SOCS proteins is conserved across different biological systems. Using in vitro human intestinal epithelial cells, mice and Drosophila melanogaster, we observed consistent negative effects upon reduction of SOCS3, which affected proliferation and cytokine profiles, tumour tolerance and, survival and the gut-brain axis, in our respective models. In both in vivo models, we were able to discover functional outcomes due to reduced SOCS3 expression, in the form of facilitation of helminth expulsion and increased stress resistance in mice and Drosophila, respectively, thus suggesting potential benefits of reduced SOCS3 in young animals whose ability to adapt to homeostatic changes is higher. Overall, we were able to deduce that SOCS3 is responsible for maintaining normal intestinal homeostasis, and ultimately host health, at a number of levels within multiple biological systems. However, our results also indicated that SOCS3 is a complex, multi-functional protein, with much investigation still needed to determine its complete role.