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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 mesenteric lymph node (MLN) CD4+ T cell subsets in Wt and Fat-1 TNBS-treated mice (black bars, n = 9–12 pooled samples/genotype comprised of 2–4 MLNs) and saline controls (grey bars, n = 4 pooled samples/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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fig3: Percentage of mesenteric lymph node (MLN) CD4+ T cell subsets in Wt and Fat-1 TNBS-treated mice (black bars, n = 9–12 pooled samples/genotype comprised of 2–4 MLNs) and saline controls (grey bars, n = 4 pooled samples/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: Following the induction of colitis, the effect of n-3 PUFA on the resident CD4+ T cell effector subset populations (i.e., Th1, Th2, Th17, and Treg) was documented both locally (colon lamina propria and MLN) and systemically (spleen). Representative dot plots for T cell subsets isolated from Wt TNBS-treated colon, MLN, and spleen are shown in Supplemental Figure  1. In all tissue sites, TNBS exposure increased the percentage of all CD4+ T cell subsets compared to the saline control group (treatment: P < 0.05, Figures 2–4). Within the colon, the percentages of proinflammatory Th17 and Th1 cells were reduced in Fat-1 mice compared to Wt (P < 0.05, Figures 2(a) and 2(b)), whereas the percentages of Th2 and Treg cells did not differ between groups (P > 0.05, Figures 2(c) and 2(d)). In the MLN, which drains and is anatomically proximal to the inflamed colon, the percentages of both Th17 and Th1 cells were reduced in Fat-1 mice compared to Wt (P < 0.05) (Figures 3(a) and 3(b)), whereas Treg and Th2 cells were unaffected (P > 0.05, Figures 3(c) and 3(d)). In the spleen, only the percentage of Th17 cells was reduced in the Fat-1 mouse (P < 0.05) compared to Wt (Figure 4(a)). Splenic Th1, Th2, and Treg cell populations did not differ between groups (P > 0.05, Figures 4(b)–4(d)). Collectively, these data demonstrate that proinflammatory Th17 and Th1 cells are selectively antagonized by n-3 PUFA in both local and systemic sites during colitis.


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 mesenteric lymph node (MLN) CD4+ T cell subsets in Wt and Fat-1 TNBS-treated mice (black bars, n = 9–12 pooled samples/genotype comprised of 2–4 MLNs) and saline controls (grey bars, n = 4 pooled samples/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

Show All Figures
getmorefigures.php?uid=PMC4127240&req=5

fig3: Percentage of mesenteric lymph node (MLN) CD4+ T cell subsets in Wt and Fat-1 TNBS-treated mice (black bars, n = 9–12 pooled samples/genotype comprised of 2–4 MLNs) and saline controls (grey bars, n = 4 pooled samples/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: Following the induction of colitis, the effect of n-3 PUFA on the resident CD4+ T cell effector subset populations (i.e., Th1, Th2, Th17, and Treg) was documented both locally (colon lamina propria and MLN) and systemically (spleen). Representative dot plots for T cell subsets isolated from Wt TNBS-treated colon, MLN, and spleen are shown in Supplemental Figure  1. In all tissue sites, TNBS exposure increased the percentage of all CD4+ T cell subsets compared to the saline control group (treatment: P < 0.05, Figures 2–4). Within the colon, the percentages of proinflammatory Th17 and Th1 cells were reduced in Fat-1 mice compared to Wt (P < 0.05, Figures 2(a) and 2(b)), whereas the percentages of Th2 and Treg cells did not differ between groups (P > 0.05, Figures 2(c) and 2(d)). In the MLN, which drains and is anatomically proximal to the inflamed colon, the percentages of both Th17 and Th1 cells were reduced in Fat-1 mice compared to Wt (P < 0.05) (Figures 3(a) and 3(b)), whereas Treg and Th2 cells were unaffected (P > 0.05, Figures 3(c) and 3(d)). In the spleen, only the percentage of Th17 cells was reduced in the Fat-1 mouse (P < 0.05) compared to Wt (Figure 4(a)). Splenic Th1, Th2, and Treg cell populations did not differ between groups (P > 0.05, Figures 4(b)–4(d)). Collectively, these data demonstrate that proinflammatory Th17 and Th1 cells are selectively antagonized by n-3 PUFA in both local and systemic sites during colitis.

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