Inhibition of the inflammatory process by n-3 PUFA in colonic cells of transgenic mice Free

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There is great interest in the role of polyunsaturated fatty acids (PUFA) in either promoting (n-6 class) or inhibiting (n-3 class) inflammation and neoplasia. In contrast to plant and nematodes, mammalian cells are devoid of a fatty acid n-3 desaturase, an enzyme able to convert n-6 PUFA to n-3 PUFA and consequently essential fatty acids must be supplied in the diet. In this study we have used transgenic mice engineered to carry the C. elegans fat-1 geneencoding a n-3 desaturase (Kang JX et al, Nature 427:504, 2004) to assess PUFA production in colonic cells. Presence of n-3 desaturase transcript in colonic cells was confirmed by RT-PCR analysis. To measure the conversion of dietary n-6 PUFA to n-3 PUFA, fat-1 mice and control littermates were fed for 7 weeks AIN-76A standard diet supplemented with 10% (w/w) safflower oil rich (76%) in n-6 polyunsaturated linoleic acid. The fatty acid profile in colon of control and transgenic mice was determined by lipid methylation and capillary gas chromatography. The results revealed different fatty acid profiles in colonic tissues of normal and fat-1 mice with significantly higher amounts of n-3 PUFA in the transgenic mice compared to wild type littermates and consequently the n-6/n-3 PUFA ratio in colonic cells of fat-1 mice was markedly lower (9.83 +/- 2.62) compared to control mice (54.5 +/- 9.24, p<0.001). These data indicate that fat-1 mice have acquired novel biochemical competence to convert dietary n-6 PUFA to n-3 PUFA. To assess dietary PUFA modulation of the inflammatory process we have induced acute and chronic colitis in normal and transgenic fat-1 mice by administration of 3% dextran sodium sulphate (DSS). These mice were fed pro-inflammatory 10% safflower diet for 7 weeks. Colonic inflammation was scored using established morphological and biochemical markers. The findings indicated a marked reduction of acute and chronic colonic inflammation in fat-1 mice (p< 0.01) compared to DSS-treated wild type littermates. Of note, attenuation of the inflammatory process in fat-1 mice was associated with a significant decrease (p<0.01) in colonic n-6 PUFA-derived PGE2._.. Cumulatively, these findings provide evidence for an anti-inflammatory action of n-3 PUFA. We have further generated compound Apc^1638N/+fat-1^+/+ mice in which the Apc 1638 mutation which induces intestinal and colonic tumorigenesis was bred into the fat-1 mouse genetic background. This novel mouse model is being studied to gain insight into the mechanistic link between inflammation and intestinal tumorigenesis and to further explore PUFA modulation of these processes. Supported by American Institute for Cancer Research Grant 04B036.