Suppression of intestinal inflammation and inflammation-driven colon cancer in mice by dietary sphingomyelin: Importance of peroxisome proliferator-activated receptor Î³ expression.
Mazzei, Joseph Cayetano
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Sphingolipid metabolites play a role in the initiation and perpetuation of inflammatory responses. Since intestinal inflammation is a driving force in the development of colon cancer, in the present study, we investigated the suppression of dextran sodium sulfate (DSS)-induced colitis by dietary sphingomyelin in mice that lack functional peroxisome proliferator-activated receptor Î³ (PPAR-Î³) in intestinal epithelial and immune cells. Dietary spingomyelin decreased colonic inflammation in mice of both genotypes but more efficiently in mice expressing PPAR-Î³. Using a real-time polymerase chain reaction array, we detected an up-regulation in genes involved in Th1 (interferon Î³) and Th17 (interleukin [IL]-17 and IL-23) responses despite the reduced inflammation. However, the genes involved in Th2 (IL-4, IL-13 and IL-13ra2) and Treg (IL-10rb) anti-inflammatory responses were up-regulated in a PPAR-Î³-dependent manner. In order to direct mechanistic studies of how PPAR-Î³ expression is involved in SM-induced suppression of DSS colitis, we investigated the effect of dietary SM in DSS-treated mice that lack PPAR-Î³ in the CD4+ T-cells. While the pathogenesis of colitis was independent of PPAR-Î³ expression in CD4+ T-cells, dietary SM decreased disease activity and colonic inflammation in mice of both genotypes but more efficiently in mice expressing PPAR-Î³, indicating both PPAR-Î³ dependent and independent signaling pathways. In conclusion, in contrast to endogenous sphingolipid metabolites, dietary SM modulated both pro- and anti-inflammatory responses at the early stages of the disease in a partially PPAR-Î³ dependent manner resulting in a suppression of inflammation that may be critical for the suppression of inflammation-driven colon cancer.
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