title: Spermidine stimulates T cell protein-tyrosine phosphatase-mediated protection of intestinal epithelial barrier function.
abstract: The gene locus encoding protein-tyrosine phosphatase non-receptor type 2 (PTPN2) has been associated with inflammatory bowel disease. Expression of the PTPN2 gene product, T cell protein-tyrosine phosphatase (TCPTP), in intestinal epithelial cells has been shown to play an important role in the protection of epithelial barrier function during periods of inflammation by acting as a negative regulator of the proinflammatory cytokine IFN-γ. Therefore, agents that increase the activity of TCPTP are of general interest as modifiers of inflammatory signaling events. A previous study demonstrated that the small molecule spermidine is a selective activator of TCPTP in vitro. The aim of this study was to investigate whether activation of TCPTP by spermidine was capable of alleviating IFN-γ-induced, proinflammatory signaling and barrier dysfunction in human intestinal epithelial cells. Studies revealed that treatment of T84 and HT29/cl.19A colonocytes with spermidine increased both TCPTP protein levels and enzymatic activity, correlating with a decrease in the phosphorylation of the signal transducers and activators of transcription 1 and 3, downstream mediators of IFN-γ signaling, upon coadministration of spermidine to IFN-γ-treated cells. On a functional level, spermidine protected barrier function in the setting of inflammation, restricting the decrease in transepithelial electrical resistance and the increase in epithelial permeability induced by IFN-γ in coincubation experiments. These data implicate spermidine as a potential therapeutic agent to treat conditions associated with elevated IFN-γ signaling and a faulty mucosal barrier.
authors.affiliation: the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla, California 92093.
authors.forename: Harrison M
authors.initials: HM
authors.lastname: Penrose
authors.affiliation: the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla, California 92093.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Marchelletta
authors.affiliation: From the Division of Biomedical Sciences, University of California, Riverside, California 92521.
authors.forename: Moorthy
authors.initials: M
authors.lastname: Krishnan
authors.affiliation: From the Division of Biomedical Sciences, University of California, Riverside, California 92521. Electronic address: declan.mccole@ucr.edu.
authors.forename: Declan F
authors.initials: DF
authors.lastname: McCole
mesh_terms: D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology*; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013095:Spermidine / Q000494:pharmacology*
chemical_list: C573415:IFNG protein, human; D007371:Interferon-gamma; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D013095:Spermidine
keywords: Epithelial Cell; Interferon; Permeability; STAT Transcription Factor; Tight Junctions
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