Abstract
Polyamines have been implicated in numerous biological processes, including inflammation and carcinogenesis. Homeostatic regulation leads to interconversion of the polyamines putrescine and the downstream metabolites spermidine and spermine. The enzyme spermine oxidase (SMOX), which back-converts spermine to spermidine, contributes to regulation of polyamine levels, but can also have other effects. We have implicated SMOX in gastric inflammation and carcinogenesis due to infection by the pathogen Helicobacter pylori. In addition, we reported that SMOX can be upregulated in humans with inflammatory bowel disease. Herein, we utilized Smox-deficient mice to examine the role of SMOX in two murine colitis models, Citrobacter rodentium infection and dextran sulfate sodium (DSS)-induced epithelial injury. In C. rodentium-infected wild-type (WT) mice, there were marked increases in colon weight/length and histologic injury, with mucosal hyperplasia and inflammatory cell infiltration; these changes were ameliorated in Smox−/− mice. In contrast, with DSS, Smox−/− mice exhibited substantial mortality, and increased body weight loss, colon weight/length, and histologic damage. In C. rodentium-infected WT mice, there were increased colonic levels of the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10, and the cytokines IL-6, TNF-α, CSF3, IFN-γ, and IL-17; each were downregulated in Smox−/− mice. In DSS colitis, increased levels of IL-6, CSF3, and IL-17 were further increased in Smox−/− mice. In both models, putrescine and spermidine were increased in WT mice; in Smox−/− mice, the main effect was decreased spermidine and spermidine/spermine ratio. With C. rodentium, polyamine levels correlated with histologic injury, while with DSS, spermidine was inversely correlated with injury. Our studies indicate that SMOX has immunomodulatory effects in experimental colitis via polyamine flux. Thus, SMOX contributes to the immunopathogenesis of C. rodentium infection, but is protective in DSS colitis, indicating the divergent effects of spermidine.
Highlights
Polyamines are pleiotropic and abundant aliphatic molecules found in all mammalian cells
The generation of spermidine protects mice from DSSinduced colitis. In accordance with this result, we found that knockout of Smox results in spermidine depletion and spermine accumulation in the colonic mucosa, which is associated with amelioration of C. rodentium colitis and worsening of DSSinduced colonic inflammation
C. rodentium infection leads to the induction of ODC in the colon of mice [7, 27], which has been further underlined in this study by the increase of putrescine concentration in the colonic tissues of infected mice
Summary
Polyamines are pleiotropic and abundant aliphatic molecules found in all mammalian cells. The back conversion of spermine to spermidine and putrescine is a critical step in the regulation of polyamine levels, notably to limit the cytotoxic effects of spermine accumulation [11] This can be achieved by two metabolic pathways: first, the enzyme spermidine/ spermine N(1)-acetyltransferase 1 catalyzes the acetylation of spermine into N(1)-acetylspermine and spermidine into N(1)-acetylspermidine; and the oxidation of these two products through the enzyme polyamine oxidase leads to the formation of spermidine and putrescine, respectively. This pathway is poorly expressed in the gastrointestinal tract during infection and inflammation [12,13,14]. We used Smox−/− mice and two models of experimental colitis: infection with Citrobacter rodentium and treatment with dextran sulfate sodium (DSS)
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