Spermidine is a positively charged polyamine, present in high quantities in foods including mushrooms, peas, cashews, and some types of meat www.selleckchem.com/products/brefeldin-a.html and cereals [20]. Because of its role in cell growth, survival and proliferation [21], [22], spermidine supplementation is being tested to treat conditions in which regeneration and healing are needed, such as impaired liver function, liver resection or burn injury [21], [23]. A role of polyamines in inflammatory responses has also been suggested. Specifically, it has been shown that spermidine is able to increase the phosphatase activity of PTPN2 in vitro in multiple cell lines including HeLa cells and human umbilical vein endothelial cells (HUVEC) [24].

Given the reported function of PTPN2 as a negative regulator of pro-inflammatory cytokine signaling [17], [19], [25], we hypothesized that pharmacological activation of PTPN2 by spermidine could potentially ameliorate pro-inflammatory responses induced by cytokines. To test our hypothesis, we first analyzed the effects of spermidine on IFN-��-induced pro-inflammatory signaling and cytokine production in human THP-1 monocytes. Monocytes/macrophages, as part of the innate immune system of the gut mucosa, play an important role in the pathogenesis of IBD [26]. We found that the activation of PTPN2 by spermidine negatively regulated IFN-��-induced signaling and cytokine secretion in THP-1 cells, conferring protection against the inflammatory responses induced by this cytokine. Subsequently, the therapeutic effect of spermidine was investigated in vivo using an experimental model of colitis.

In mice with dextran sodium sulfate (DSS)-induced colitis, disease activity was reduced upon treatment with spermidine, supporting its anti-inflammatory potential as a therapy to treat IBD. Methods Induction of Colitis and Spermidine Treatment in Mice Animal experiments were carried out according to Swiss animal welfare laws and were approved by the veterinary authorities of Zurich, Switzerland (Kanton Z��rich Gesundheitsdirektion Veterin?ramt, approval no. 54/2011). Due to the approval of the veterinary authorities of Z��rich, no further approval by an Institutional Animal Care and Use Committee (IACUC) or ethics committee was necessary. Seven- to eight-week-old female C57BL/6J-Crl mice were used for the experiments and housed in a specified pathogen-free facility in individually ventilated cages.

Acute colitis was induced with 2.5% DSS (MP Biomedicals, Illkirch, France) in drinking water during 8 days [27]. The animals were randomly divided into two DSS groups and two water control groups with six individuals each. For treatment, spermidine was dissolved in water GSK-3 at 0.1 M and 150 ��l administered by oral gavage. The non-treated control groups received 150 ��l of water by oral gavage.