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VSL#3 Stimulates TCPTP and Attenuates IFN-gamma Induced Epithelial Barrier Permeability /


In Inflammatory Bowel Disease (IBD), the colon and small intestine are chronically inflamed due, at least in part, to increased epithelial permeability and an inappropriate immune response to luminal antigens. IFN-gamma is a prominent pro-inflammatory cytokine that increases permeability of the intestinal epithelium and T-Cell Protein Tyrosine Phosphatase (TCPTP) is a negative regulator of IFN-gamma signaling. This research explores the effects of a probiotic preparation on TCPTP abundance, resolution of inflammatory signaling, and intestinal epithelial permeability by studying a probiotic blend called VSL#3. Research showed that in T84 colonic epithelial cells, VSL#3 was able to increase TCPTP protein levels by 150 ± 3% and enzymatic activity by 100 ± 5% (106 CFU/mL for 9 hours). Moreover, VSL#3 was able to decrease epithelial monolayer permeability by 25 ± 2% over 9 hours (106 CFU/mL). When IFN-gamma and VSL#3 were co-incubated, VSL#3 attenuated the increase in permeability that resulted from 24 hours pre-treatment of T84 cells with IFN-gamma by 120 ± 2%. Moreover, levels of phosphorylated STAT-1 (a downstream effect of IFN-gamma signaling) decreased when VSL#3 and IFN-gamma were co- incubated and TCPTP levels showed an increase as VSL#3 doses were increased. Results were inconclusive as to whether VSL#3's effects on transepithelial resistance in IFN-gamma pre-treated cells were TCPTP-mediated because the TCPTP inhibitor failed to display its expected action. Overall, the findings of this thesis indicate that VSL#3 can repair epithelial permeability defects caused by IFN- gamma and this may be due in part to upregulation of a negative regulator of IFN-gamma signaling, TCPTP

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