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

Imtiyaz Thagia,Kathryn J Else,Rachael J Rigby,Emily Smith,Elisabeth J Shaw

doi:10.1152/ajpgi.00214.2014

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.

Highlights

THE HOMEOSTATIC INFLUENCE of microbiota on intestinal epithelial cell (IEC) turnover occurs in an actively regulated environment, dictated by signals between the microbiota, IEC, and IEC-conditioned components of the immune system [2, 23]
We have shown that Suppressor of cytokine signaling-3 (SOCS3) promotes TLR5-induced increases in TNF-␣, an important pathological cytokine in inflammatory bowel disease (IBD)
TNF-␣ disrupts intestinal epithelial barrier function [29] and emerging evidence suggests that flagellin is a major driver of TNF-␣ in pathological inflammation [5]

Summary

Introduction

THE HOMEOSTATIC INFLUENCE of microbiota on intestinal epithelial cell (IEC) turnover occurs in an actively regulated environment, dictated by signals between the microbiota, IEC, and IEC-conditioned components of the immune system [2, 23]. TLR signaling pathways are important activators of NF-␬B, driving the expression of a number of “proinflammatory” genes such as TNF-␣, IL-6, and IL-8 essential for tissue repair and maintenance of barrier function [26]. Suppressor of cytokine signaling-3 (SOCS3), an endogenous modulator of IEC turnover, is upregulated in IBD [15, 24]. TNFR2 is upregulated in IBD and in models of inflammation-associated cancer [6, 16, 18], regarded to be in response to increased inflammatory cytokines in the mucosa, as TNF-␣ and IL-6 induce TNFR2 in colon cancer cells [9, 16]. We propose that SOCS3, ostensibly an endogenous inhibitor of inflammatory signaling and proliferation, paradoxically promotes intestinal inflammation, possibly through limiting microbial-induced TNFR2 expression, enhancing TNF-␣ production and limiting epithelial barrier repair

Methods

Results

Conclusion