Spermidine Stimulates Protein Tyrosine Phosphatase N2-Mediated Protection of Intestinal Epithelial Barrier Function

Abstract

Genome wide association studies (GWAS) have revealed that single nucleotide polymorphisms (SNP) in the gene locus encoding a particular phosphatase, protein tyrosine phosphatase non receptor type 2 (PTPN2), are associated with the chronic intestinal inflammatory condition, Crohns disease. PTPN2 is ubiquitously expressed. However, its expression in intestinal epithelial cells (IEC) 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, interferon-γ (IFN-γ). Therefore, agents that increase the activity of PTPN2 are of general interest as modifiers of inflammatory signaling events.

A recent study demonstrated that the small molecule, spermidine, is a selective activator of PTPN2 in vitro. Here, I describe the effects of spermidine on PTPN2 expression and activity, as well as its effect on IFN-γ signaling and barrier function in the human colonic epithelial cell line, T₈₄. My studies revealed that spermidine increased both PTPN2 protein levels and enzymatic activity, correlating with a decrease in the phosphorylation of the signal transducers and activators of transcription (STAT)1 and 3, downstream mediators of IFN-γ signaling, upon coadministration of spermidine to IFN-γ treated cells. Additionally, spermidine protected barrier function in the setting of inflammation, restricting the decrease in transepithelial electrical resistance (TER) induced by IFN-γ in coincubation experiments. Spermidines ability to increase PTPN2 levels and activity, as well as reduce IFN-γ signaling in IECs, implicate spermidine as a potential therapeutic agent for treating conditions associated with dysregulated IFN-γ signaling and a faulty mucosal barrier.