Limits...
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.

Show MeSH

Related in: MedlinePlus

The degree of distal colon histological injury/damage in Fat-1 and Wt TNBS-treated mice (n = 8-9/genotype). ((a) and (b)) Representative images (100x magnification, scale bar = 100 μm) of TNBS-treated Fat-1 and Wt mice, (c) Wt saline control treated (injury score = 0) distal colons, and (d) injury scores (0–3) in the distal colon from Wt and Fat-1 TNBS-treated mice, respectively. Data were analyzed using the Kruskal-Wallis test (P ≤ 0.05). Median values are shown and significant differences between genotypes are marked with an asterisk (P ≤ 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4127240&req=5

fig1: The degree of distal colon histological injury/damage in Fat-1 and Wt TNBS-treated mice (n = 8-9/genotype). ((a) and (b)) Representative images (100x magnification, scale bar = 100 μm) of TNBS-treated Fat-1 and Wt mice, (c) Wt saline control treated (injury score = 0) distal colons, and (d) injury scores (0–3) in the distal colon from Wt and Fat-1 TNBS-treated mice, respectively. Data were analyzed using the Kruskal-Wallis test (P ≤ 0.05). Median values are shown and significant differences between genotypes are marked with an asterisk (P ≤ 0.05).

Mentions: Body weight and colon length at the time of sacrifice are shown in Supplemental Table  1 (see Supplementary Material available online at http://dx.doi.org/10.1155/2014/917149). Compared to saline controls, TNBS-treated mice exhibited lower body weights and colon shortening, but they did not differ between genotypes (P > 0.05). The degree of colon injury following exposure to TNBS was assessed based on colonic histological changes in a blinded manner by a board-certified pathologist (B. Weeks). Representative distal colon images from Wt and Fat-1 saline control and TNBS-treated mice are shown (Figures 1(a)–1(c)). The saline control treatment did not induce colonic damage and both Wt and Fat-1 mice exhibited an injury score of 0 in all regions of the colon. In TNBS-treated mice, injury scores were lower in the proximal and middle regions of the colon compared to the distal colon; however, they did not differ between Wt and Fat-1 mice (proximal colon, P = 0.45, and middle colon, P = 0.54, results not shown). However, within the distal colon (site of TNBS administration via rectal enema), the degree of colonic injury was significantly reduced in Fat-1 mice compared to Wt (P = 0.05, Figure 1(d)). This outcome is consistent with the TNBS model exerting the majority of histopathological damage within the distal colon [55] and with the ability of n-3 PUFA to enhance the resolution of inflammatory processes and reduce colonic injury by promoting mucosal repair [47, 56].


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)

The degree of distal colon histological injury/damage in Fat-1 and Wt TNBS-treated mice (n = 8-9/genotype). ((a) and (b)) Representative images (100x magnification, scale bar = 100 μm) of TNBS-treated Fat-1 and Wt mice, (c) Wt saline control treated (injury score = 0) distal colons, and (d) injury scores (0–3) in the distal colon from Wt and Fat-1 TNBS-treated mice, respectively. Data were analyzed using the Kruskal-Wallis test (P ≤ 0.05). Median values are shown and significant differences between genotypes are marked with an asterisk (P ≤ 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: The degree of distal colon histological injury/damage in Fat-1 and Wt TNBS-treated mice (n = 8-9/genotype). ((a) and (b)) Representative images (100x magnification, scale bar = 100 μm) of TNBS-treated Fat-1 and Wt mice, (c) Wt saline control treated (injury score = 0) distal colons, and (d) injury scores (0–3) in the distal colon from Wt and Fat-1 TNBS-treated mice, respectively. Data were analyzed using the Kruskal-Wallis test (P ≤ 0.05). Median values are shown and significant differences between genotypes are marked with an asterisk (P ≤ 0.05).
Mentions: Body weight and colon length at the time of sacrifice are shown in Supplemental Table  1 (see Supplementary Material available online at http://dx.doi.org/10.1155/2014/917149). Compared to saline controls, TNBS-treated mice exhibited lower body weights and colon shortening, but they did not differ between genotypes (P > 0.05). The degree of colon injury following exposure to TNBS was assessed based on colonic histological changes in a blinded manner by a board-certified pathologist (B. Weeks). Representative distal colon images from Wt and Fat-1 saline control and TNBS-treated mice are shown (Figures 1(a)–1(c)). The saline control treatment did not induce colonic damage and both Wt and Fat-1 mice exhibited an injury score of 0 in all regions of the colon. In TNBS-treated mice, injury scores were lower in the proximal and middle regions of the colon compared to the distal colon; however, they did not differ between Wt and Fat-1 mice (proximal colon, P = 0.45, and middle colon, P = 0.54, results not shown). However, within the distal colon (site of TNBS administration via rectal enema), the degree of colonic injury was significantly reduced in Fat-1 mice compared to Wt (P = 0.05, Figure 1(d)). This outcome is consistent with the TNBS model exerting the majority of histopathological damage within the distal colon [55] and with the ability of n-3 PUFA to enhance the resolution of inflammatory processes and reduce colonic injury by promoting mucosal repair [47, 56].

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