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

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

Intestinal epithelial Suppressor of Cytokine Signaling (SOCS) 3 enhances microbial induced inflammatory TNFα, contributing to epithelial barrier dysfunction

A single layer of intestinal epithelial cells (IEC) lines the entire GI tract and provides the first line of defence and barrier against an abundance of microbial stimuli. IEC homeostasis and repair are mediated through microbe-sensing Toll-like receptor (TLR)-induced inflammatory pathways. Increasing evidence supports a role of suppressor of cytokine signaling 3 (SOCS3) as a modulator of IEC turnover, balancing controlled repair and replenishment with excessive IEC proliferation predisposing to dysplasia and cancer. Our data indicate that SOCS3 can limit microbial-induced epithelial repair, promote TNFα, possibly through limiting TNFR2 expression in intestinal epithelial cells (IEC). Activation of TLR5 signalling pathways, compared with other TLR, increase TNFα mRNA in a dose dependent manner and SOCS3 enhances TLR5-induced TNFα. We also show that flagellin promotes transcription of TNFR2 and that SOCS3 may limit this expression, presenting a mechanism of SOCS3 action. Our data also supports the role of microbial ligands in epithelial wound healing and suggests that a functional consequence of increased TNFα is reduced wound healing. These results provide further evidence to support the regulatory role of epithelial SOCS3 in intestinal health and suggest that the increased expression of SOCS3 observed in IBD may serve to perpetuate 'inflammation' by promoting TNFα production and limiting epithelial repair in response to commensal microflora