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Intestinal epithelial suppressor of cytokine signaling 3 enhances microbial-induced inflammatory tumor necrosis factor-α, contributing to epithelial barrier dysfunction.

American journal of physiology. Gastrointestinal and liver physiology (2014-11-08)
Imtiyaz Thagia, Elisabeth J Shaw, Emily Smith, Kathryn J Else, Rachael J Rigby
ABSTRACT

A single layer of intestinal epithelial cells (IEC) lines the entire gastrointestinal tract and provides the first line of defense 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 IEC repair, potentially through promoting tumor necrosis factor-α (TNF-α) and limiting TNFR2 expression. Activation of TLR5 signaling pathways, compared with other TLR, increases TNF-α mRNA in a dose-dependent manner and SOCS3 enhances TLR5-induced TNF-α. We also show that flagellin promotes transcription of TNFR2 and that SOCS3 limits this expression, presenting a mechanism of SOCS3 action. Our data also support the role of microbial ligands in epithelial wound healing and suggest that a functional consequence of increased TNF-α 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 TNF-α production and limiting epithelial repair in response to commensal microflora.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
CACO-2, Caucasian colon adenocarcinoma
CACO-2 Cell Line human, 86010202, from human colon(Caucasian colon adenocarcinoma)
SW480 Cell Line human, 87092801