Background
VSL#3 is a probiotic compound that has been used in the treatment of Inflammatory Bowel Disease (IBD). T-cell protein tyrosine phosphatase (TCPTP) is the protein product of the IBD candidate gene, PTPN2, and we have previously shown that it protects epithelial barrier function. The aim of this study was to investigate if VSL#3 improves intestinal epithelial barrier function against the effects of the IBD associated pro-inflammatory cytokine, interferon-gamma (IFN-γ) via activation of TCPTP.
Methods
Polarized monolayers of T84 intestinal epithelial cell (IEC) were treated with increasing concentrations of VSL#3 to determine effects on TCPTP expression and enzymatic activity. Therapeutic effects of VSL#3 against barrier disruption by IFN-γ were measured by transepithelial electrical resistance (TER) and FITC-dextran permeability. A novel TCPTP-deficient HT-29 IEC line was generated to study the role of TCPTP in mediating the effects of VSL#3. Tight junction protein distribution was assessed by confocal microscopy.
Results
VSL#3 increased TCPTP protein levels and enzymatic activity, correlating with a VSL#3-induced decrease in IFN-γ signaling. VSL#3 corrected the decrease in TER and the increase in epithelial permeability induced by IFN-γ. Moreover, the restorative effect of VSL#3 against IFN-γ signaling, epithelial permeability defects, altered expression and localization of the tight junction proteins claudin-2, occludin and ZO-1, were not realized in stable TCPTP/(PTPN2)-deficient HT-29 intestinal epithelial cells.
Conclusion
VSL#3 reduces IFN-γ signaling and IFN-γ-induced epithelial barrier defects in a TCPTP-dependent manner. These data point to a key role for TCPTP as a therapeutic target for restoration of barrier function by probiotics.
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