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

Thagia, Imtiyaz and Shaw, Elisabeth J. and Smith, Emily and Else, Kathryn J. and Rigby, Rachael Jane (2015) Intestinal epithelial Suppressor of Cytokine Signaling (SOCS) 3 enhances microbial induced inflammatory TNFα, contributing to epithelial barrier dysfunction. American Journal of Physiology-Gastrointestinal and Liver Physiology, 308 (1). G25-G31. ISSN 0193-1857

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Abstract

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.

Item Type:
Journal Article
Journal or Publication Title:
American Journal of Physiology-Gastrointestinal and Liver Physiology
Additional Information:
Copyright © 2015 the American Physiological Society Licensed under Creative Commons Attribution CC-BY 3.0: © the American Physiological Society.
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2737
Subjects:
ID Code:
71873
Deposited By:
Deposited On:
26 Nov 2014 16:47
Refereed?:
Yes
Published?:
Published
Last Modified:
08 Aug 2020 04:05