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Antagonizing arachidonic acid-derived eicosanoids reduces inflammatory Th17 and Th1 cell-mediated inflammation and colitis severity.

Monk JM, Turk HF, Fan YY, Callaway E, Weeks B, Yang P, McMurray DN, Chapkin RS - Mediators Inflamm. (2014)

Bottom Line: 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 of Th17 cell markers (IL-17A, RORγτ, 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 PGE2 levels via different mechanisms.Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation.

View Article: PubMed Central - PubMed

Affiliation: Program in Integrative Nutrition & Complex Diseases, Center for Translational Environmental Health Research, Texas A&M University, College Station, TX, USA ; Department of Nutrition & Food Science, Texas A&M University, College Station, TX, USA.

ABSTRACT
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 E2 (PGE2), promote Th17 cell-mediated inflammation, while n-3 PUFA antagonize both Th17 and Th1 cells and suppress PGE2 levels. We utilized two genetic mouse models, which differentially antagonize PGE2 levels, to examine the effect on Th17 cells and disease outcomes in trinitrobenzene sulfonic acid- (TNBS-) induced colitis. Fat-1 mice contain the ω3 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 Δ5 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 of Th17 cell markers (IL-17A, RORγτ, 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 PGE2 levels via different mechanisms. Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation.

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Percentage of splenic CD4+ T cell subsets in Wt, Het, and Null Fads1 TNBS-treated mice (black bars, n = 6–9 mice/genotype) and saline controls (grey bars, n = 3-4 mice/genotype). (a) Th17 cells (CD4+ IL-17A+), (b) Th1 cells (CD4+ IFNγ+), (c) Th2 cells (CD4+ IL-4+), and (d) Tregs (CD4+ Foxp3+). Data were analyzed by two-way ANOVA (main effects: genotype and treatment). Bars represent means ± SEM. Bars not sharing a symbol differ (P ≤ 0.05).
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fig6: Percentage of splenic CD4+ T cell subsets in Wt, Het, and Null Fads1 TNBS-treated mice (black bars, n = 6–9 mice/genotype) and saline controls (grey bars, n = 3-4 mice/genotype). (a) Th17 cells (CD4+ IL-17A+), (b) Th1 cells (CD4+ IFNγ+), (c) Th2 cells (CD4+ IL-4+), and (d) Tregs (CD4+ Foxp3+). Data were analyzed by two-way ANOVA (main effects: genotype and treatment). Bars represent means ± SEM. Bars not sharing a symbol differ (P ≤ 0.05).

Mentions: Due to limitations in mouse numbers and the necessity to pool colons to obtain sufficient cells for analysis, quantification of T cell subsets in the colon and MLN was not possible. Therefore, changes in systemic T cell subsets (i.e., Th1, Th2, Th17, and Treg) following exposure to TNBS were determined in the spleen and representative dot plots are shown in Supplemental Figure  2. As expected, TNBS treatment increased all splenic CD4+ T cell subsets compared to saline controls (P < 0.05). The percentages of splenic Th17 and Th1 cells were reduced in Fads1 Nullmice compared to both Wt and Het mice (P < 0.05, Figures 6(a) and 6(b)). Interestingly, the percentage of splenic Th2 cells was also reduced in the Fads1 Null mouse compared to both Wt and Het TNBS-treated mice (P = 0.04, Figure 6(c)), whereas splenic Tregs were unaffected (Wt versus Null, P > 0.05, Figure 6(d)). There was no difference between Wt and Het mice in the percentage of splenic Th17, Th1, and Th2 cells (Figures 6(a)–6(c)), whereas the percentage of splenic Treg cells was increased in Het mice compared to both Wt and Fads1 Null (P = 0.008, Figure 6(d)).


Antagonizing arachidonic acid-derived eicosanoids reduces inflammatory Th17 and Th1 cell-mediated inflammation and colitis severity.

Monk JM, Turk HF, Fan YY, Callaway E, Weeks B, Yang P, McMurray DN, Chapkin RS - Mediators Inflamm. (2014)

Percentage of splenic CD4+ T cell subsets in Wt, Het, and Null Fads1 TNBS-treated mice (black bars, n = 6–9 mice/genotype) and saline controls (grey bars, n = 3-4 mice/genotype). (a) Th17 cells (CD4+ IL-17A+), (b) Th1 cells (CD4+ IFNγ+), (c) Th2 cells (CD4+ IL-4+), and (d) Tregs (CD4+ Foxp3+). Data were analyzed by two-way ANOVA (main effects: genotype and treatment). Bars represent means ± SEM. Bars not sharing a symbol differ (P ≤ 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig6: Percentage of splenic CD4+ T cell subsets in Wt, Het, and Null Fads1 TNBS-treated mice (black bars, n = 6–9 mice/genotype) and saline controls (grey bars, n = 3-4 mice/genotype). (a) Th17 cells (CD4+ IL-17A+), (b) Th1 cells (CD4+ IFNγ+), (c) Th2 cells (CD4+ IL-4+), and (d) Tregs (CD4+ Foxp3+). Data were analyzed by two-way ANOVA (main effects: genotype and treatment). Bars represent means ± SEM. Bars not sharing a symbol differ (P ≤ 0.05).
Mentions: Due to limitations in mouse numbers and the necessity to pool colons to obtain sufficient cells for analysis, quantification of T cell subsets in the colon and MLN was not possible. Therefore, changes in systemic T cell subsets (i.e., Th1, Th2, Th17, and Treg) following exposure to TNBS were determined in the spleen and representative dot plots are shown in Supplemental Figure  2. As expected, TNBS treatment increased all splenic CD4+ T cell subsets compared to saline controls (P < 0.05). The percentages of splenic Th17 and Th1 cells were reduced in Fads1 Nullmice compared to both Wt and Het mice (P < 0.05, Figures 6(a) and 6(b)). Interestingly, the percentage of splenic Th2 cells was also reduced in the Fads1 Null mouse compared to both Wt and Het TNBS-treated mice (P = 0.04, Figure 6(c)), whereas splenic Tregs were unaffected (Wt versus Null, P > 0.05, Figure 6(d)). There was no difference between Wt and Het mice in the percentage of splenic Th17, Th1, and Th2 cells (Figures 6(a)–6(c)), whereas the percentage of splenic Treg cells was increased in Het mice compared to both Wt and Fads1 Null (P = 0.008, Figure 6(d)).

Bottom Line: 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 of Th17 cell markers (IL-17A, RORγτ, 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 PGE2 levels via different mechanisms.Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation.

View Article: PubMed Central - PubMed

Affiliation: Program in Integrative Nutrition & Complex Diseases, Center for Translational Environmental Health Research, Texas A&M University, College Station, TX, USA ; Department of Nutrition & Food Science, Texas A&M University, College Station, TX, USA.

ABSTRACT
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 E2 (PGE2), promote Th17 cell-mediated inflammation, while n-3 PUFA antagonize both Th17 and Th1 cells and suppress PGE2 levels. We utilized two genetic mouse models, which differentially antagonize PGE2 levels, to examine the effect on Th17 cells and disease outcomes in trinitrobenzene sulfonic acid- (TNBS-) induced colitis. Fat-1 mice contain the ω3 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 Δ5 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 of Th17 cell markers (IL-17A, RORγτ, 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 PGE2 levels via different mechanisms. Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation.

Show MeSH
Related in: MedlinePlus