Antagonizing Arachidonic Acid-Derived Eicosanoids Reduces Inflammatory Th17 and Th1 Cell-Mediated Inflammation and Colitis Severity

During colitis, activation of two inflammatory T cell subsets, Th17 and Th1 cells, promotes ongoing intestinal inflammatory responses. n-6 polyunsaturated fatty acid- (PUFA-) derived eicosanoids, such as prostaglandin E-2 (PGE(2)), promote Th17 cell-mediated inflammation, while n-3 PUFA antagonize both Th17 and Th1 cells and suppress PGE(2) levels. We utilized two genetic mouse models, which differentially antagonize PGE(2) levels, to examine the effect on Th17 cells and disease outcomes in trinitrobenzene sulfonic acid-(TNBS-) induced colitis. Fat-1 mice contain the omega 3 desaturase gene from C. elegans and synthesize n-3 PUFA de novo, thereby reducing the biosynthesis of n-6 PUFA-derived eicosanoids. In contrast, Fads1 Null mice contain a disrupted Delta 5 desaturase gene and produce lower levels of n-6 PUFA-derived eicosanoids. Compared to Wt littermates, Fat-1 and Fads1 Null mice exhibited a similar colitic phenotype characterized by reduced colonic mucosal inflammatory eicosanoid levels and mRNA expression ofTh17 cell markers (IL-17A, ROR gamma tau, and IL-23), decreased percentages of Th17 cells and, improved colon injury scores (P <= 0.05). Thus, during colitis, similar outcomes were obtained in two genetically distinct models, both of which antagonize PGE(2) levels via different mechanisms. Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion ofTh17 cell-mediated colonic inflammation.