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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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Distal colon histological injury/damage scores assessed in Wt, Het, and Null Fads1 TNBS-treated mice (n = 8–10/genotype) in a blinded manner by a board-certified pathologist (B. Weeks). ((a)–(c)) Representative images (100x magnification, scale bar = 100 μm) of Wt, Het, and Null Fads1 TNBS-treated distal colons, respectively. (d) Distal colon injury scores (0–3). Data were analyzed using the Kruskal-Wallis test (P ≤ 0.05) followed by Wilcoxon two-sample testing. Median values are shown and significant differences between genotypes are marked by an asterisk (P ≤ 0.05).
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fig5: Distal colon histological injury/damage scores assessed in Wt, Het, and Null Fads1 TNBS-treated mice (n = 8–10/genotype) in a blinded manner by a board-certified pathologist (B. Weeks). ((a)–(c)) Representative images (100x magnification, scale bar = 100 μm) of Wt, Het, and Null Fads1 TNBS-treated distal colons, respectively. (d) Distal colon injury scores (0–3). Data were analyzed using the Kruskal-Wallis test (P ≤ 0.05) followed by Wilcoxon two-sample testing. Median values are shown and significant differences between genotypes are marked by an asterisk (P ≤ 0.05).

Mentions: The degree of TNBS-induced colon injury was assessed histologically in Fads1 Wt, Het, and Null mice (representative distal colon images, Figures 5(a)–5(c)). Histological injury scores were 0 throughout the colon in saline control treated mice from all three Fads1 genotypes. Within TNBS-treated mice, the degree of colon injury did not differ between genotypes in the proximal (P = 0.10) and middle (P = 0.31) regions of the colon. However, distal colon injury scores were reduced significantly in Fads1 Null mice compared to both Wt and Het mice (P = 0.04) (Figure 5(d)). Colon length and final body weights were lower in TNBS-treated mice compared to saline controls but did not differ between genotypes (P > 0.05) as shown in Supplemental Table  2. These data suggest that antagonizing colon mucosal eicosanoid levels via AA deficiency reduces the severity of colon histological structural damage induced during TNBS 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)

Distal colon histological injury/damage scores assessed in Wt, Het, and Null Fads1 TNBS-treated mice (n = 8–10/genotype) in a blinded manner by a board-certified pathologist (B. Weeks). ((a)–(c)) Representative images (100x magnification, scale bar = 100 μm) of Wt, Het, and Null Fads1 TNBS-treated distal colons, respectively. (d) Distal colon injury scores (0–3). Data were analyzed using the Kruskal-Wallis test (P ≤ 0.05) followed by Wilcoxon two-sample testing. Median values are shown and significant differences between genotypes are marked by an asterisk (P ≤ 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4127240&req=5

fig5: Distal colon histological injury/damage scores assessed in Wt, Het, and Null Fads1 TNBS-treated mice (n = 8–10/genotype) in a blinded manner by a board-certified pathologist (B. Weeks). ((a)–(c)) Representative images (100x magnification, scale bar = 100 μm) of Wt, Het, and Null Fads1 TNBS-treated distal colons, respectively. (d) Distal colon injury scores (0–3). Data were analyzed using the Kruskal-Wallis test (P ≤ 0.05) followed by Wilcoxon two-sample testing. Median values are shown and significant differences between genotypes are marked by an asterisk (P ≤ 0.05).
Mentions: The degree of TNBS-induced colon injury was assessed histologically in Fads1 Wt, Het, and Null mice (representative distal colon images, Figures 5(a)–5(c)). Histological injury scores were 0 throughout the colon in saline control treated mice from all three Fads1 genotypes. Within TNBS-treated mice, the degree of colon injury did not differ between genotypes in the proximal (P = 0.10) and middle (P = 0.31) regions of the colon. However, distal colon injury scores were reduced significantly in Fads1 Null mice compared to both Wt and Het mice (P = 0.04) (Figure 5(d)). Colon length and final body weights were lower in TNBS-treated mice compared to saline controls but did not differ between genotypes (P > 0.05) as shown in Supplemental Table  2. These data suggest that antagonizing colon mucosal eicosanoid levels via AA deficiency reduces the severity of colon histological structural damage induced during TNBS 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