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Genetic deletion of IL-25 (IL-17E) confers resistance to dextran sulfate sodium-induced colitis in mice.

Wang AJ, Smith A, Li Y, Urban JF, Ramalingam TR, Wynn TA, Lu N, Shea-Donohue T, Yang Z, Zhao A - Cell Biosci (2014)

Bottom Line: Several previous studies reported inconsistent results on the role of exogenous IL-25 in development of colonic inflammation and none were performed in animals with a genetic deletion of IL-25.Finally, stimulation of T84 colonic epithelial cells with IL-25 up-regulated the expression of IL-33 and several pro-inflammatory cytokines.The present study suggests that IL-25 may contribute to the pathogenesis of inflammatory bowel disease in at least a subgroup of patients.

View Article: PubMed Central - PubMed

Affiliation: Departments of Radiation Oncology and Medicine, University of Maryland School of Medicine, 10 S. Pine Street, MSTF, Room 7-00D, Baltimore, MD 21201 USA ; Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006 China.

ABSTRACT

Background: IL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote type 2 while suppressing Th1 and Th17 responses. Several previous studies reported inconsistent results on the role of exogenous IL-25 in development of colonic inflammation and none were performed in animals with a genetic deletion of IL-25. We investigated the contribution of endogenous IL-25 to DSS-induced colitis using mice deficient in IL-25.

Results: Mice were exposed to DSS in drinking water ad libitum either for seven days (acute) or for three cycles of seven days with DSS followed by 14 days without DSS (chronic) to induce colitis, respectively. The loss of body weight, appearance of diarrhea and bloody stools, and shortening of colon length were significantly less pronounced in IL-25(-/-) mice compared to WT mice after exposure to acute DSS. Histological examination showed that DSS-treated IL-25(-/-) mice had only mild inflammation in the colon, while severe inflammation developed in DSS-treated WT mice. A significant up-regulation of IL-33 was observed in acute DSS-treated WT but not in the IL-25(-/-) mice. There was significantly lower expression of pro-inflammatory cytokines in the colon of acute DSS-treated IL-25(-/-) compared to WT mice. IL-25(-/-) mice were also partially protected from chronic DSS challenge especially during the first 2 cycles of DSS exposure. In contrast to IL-25(-/-) mice, IL-13(-/-) mice were more susceptible to DSS-induced colitis. Finally, stimulation of T84 colonic epithelial cells with IL-25 up-regulated the expression of IL-33 and several pro-inflammatory cytokines.

Conclusions: These data indicate that endogenous IL-25 acts as a pro-inflammatory factor in DSS-induced colitis, which is unlikely to be mediated by IL-13 but possibly the induction of IL-33 and other pro-inflammatory mediators from colonic epithelial cells. The present study suggests that IL-25 may contribute to the pathogenesis of inflammatory bowel disease in at least a subgroup of patients.

No MeSH data available.


Related in: MedlinePlus

Mice genetically deficient in IL-25 are partially protected from chronic dextran sulfate sodium (DSS)-induced colitis. Mice were exposed to three cycles of DSS treatment. Each cycle of DSS involved seven days of DSS followed by 14 days on regular water. Mice were euthanized at the eighth day of the third DSS cycle. (A) Body weight change expressed as the percentage of initial body weight at day 0; (B) Clinical disease activity based on stool consistency (0–3), presence of blood in stool (0–2), and general appearance (0–2); (C) Colon length at euthanasia; (D) Representative H&E-stained colon sections (100X) and the histological activity index from a total score of epithelial damage (0–4) and inflammatory cell infiltration (0–4). Data are mean ± SEM and are representatives of two independent experiments with five or six mice per group. *P < 0.05 versus the respective WT.
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Fig2: Mice genetically deficient in IL-25 are partially protected from chronic dextran sulfate sodium (DSS)-induced colitis. Mice were exposed to three cycles of DSS treatment. Each cycle of DSS involved seven days of DSS followed by 14 days on regular water. Mice were euthanized at the eighth day of the third DSS cycle. (A) Body weight change expressed as the percentage of initial body weight at day 0; (B) Clinical disease activity based on stool consistency (0–3), presence of blood in stool (0–2), and general appearance (0–2); (C) Colon length at euthanasia; (D) Representative H&E-stained colon sections (100X) and the histological activity index from a total score of epithelial damage (0–4) and inflammatory cell infiltration (0–4). Data are mean ± SEM and are representatives of two independent experiments with five or six mice per group. *P < 0.05 versus the respective WT.

Mentions: We next utilized a model of chronic DSS-induced colitis to further evaluate the role of IL-25. As expected, both WT and IL-25−/− mice lost body weight compared to vehicle-treated controls, but gained body weight when DSS treatment was interrupted. Notably, IL-25−/− mice lost significantly less body weight during the first two cycles of DSS exposure and recovered faster after the switch back to water compared to DSS-treated WT mice (Figure 2A). In addition, lower disease activity scores were recorded in IL-25−/− mice than in WT mice when examined at the end of first (day 7) and second (day 28) cycle of DSS exposure (Figure 2B). However, as the third cycle of DSS began, both IL-25−/− mice and WT mice lost body weight in a similar more rapid rate than observed in the first two cycles of DSS exposure. No differences in weight loss between the DSS-treated IL-25−/− and WT mice were detected during the third cycle of DSS exposure, and the total clinical scores were similar at day 49 (Figure 2B). At euthanasia, both IL-25−/− and WT mice treated with DSS had a similar shortening of colon length (Figure 2C), and microscopic examination showed complete loss of crypts as well as extensive inflammatory cell infiltration in the muscularis mucosa, submucosa, and muscularis externa (Figure 2D). Dramatic and similar smooth muscle hyperplasia/hypertrophy was also evident in both IL-25−/− and WT mice. These results are consistent with the notion that mice genetically deficient in IL-25 are only partially protected from DSS-induced chronic colitis.Figure 2


Genetic deletion of IL-25 (IL-17E) confers resistance to dextran sulfate sodium-induced colitis in mice.

Wang AJ, Smith A, Li Y, Urban JF, Ramalingam TR, Wynn TA, Lu N, Shea-Donohue T, Yang Z, Zhao A - Cell Biosci (2014)

Mice genetically deficient in IL-25 are partially protected from chronic dextran sulfate sodium (DSS)-induced colitis. Mice were exposed to three cycles of DSS treatment. Each cycle of DSS involved seven days of DSS followed by 14 days on regular water. Mice were euthanized at the eighth day of the third DSS cycle. (A) Body weight change expressed as the percentage of initial body weight at day 0; (B) Clinical disease activity based on stool consistency (0–3), presence of blood in stool (0–2), and general appearance (0–2); (C) Colon length at euthanasia; (D) Representative H&E-stained colon sections (100X) and the histological activity index from a total score of epithelial damage (0–4) and inflammatory cell infiltration (0–4). Data are mean ± SEM and are representatives of two independent experiments with five or six mice per group. *P < 0.05 versus the respective WT.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4417544&req=5

Fig2: Mice genetically deficient in IL-25 are partially protected from chronic dextran sulfate sodium (DSS)-induced colitis. Mice were exposed to three cycles of DSS treatment. Each cycle of DSS involved seven days of DSS followed by 14 days on regular water. Mice were euthanized at the eighth day of the third DSS cycle. (A) Body weight change expressed as the percentage of initial body weight at day 0; (B) Clinical disease activity based on stool consistency (0–3), presence of blood in stool (0–2), and general appearance (0–2); (C) Colon length at euthanasia; (D) Representative H&E-stained colon sections (100X) and the histological activity index from a total score of epithelial damage (0–4) and inflammatory cell infiltration (0–4). Data are mean ± SEM and are representatives of two independent experiments with five or six mice per group. *P < 0.05 versus the respective WT.
Mentions: We next utilized a model of chronic DSS-induced colitis to further evaluate the role of IL-25. As expected, both WT and IL-25−/− mice lost body weight compared to vehicle-treated controls, but gained body weight when DSS treatment was interrupted. Notably, IL-25−/− mice lost significantly less body weight during the first two cycles of DSS exposure and recovered faster after the switch back to water compared to DSS-treated WT mice (Figure 2A). In addition, lower disease activity scores were recorded in IL-25−/− mice than in WT mice when examined at the end of first (day 7) and second (day 28) cycle of DSS exposure (Figure 2B). However, as the third cycle of DSS began, both IL-25−/− mice and WT mice lost body weight in a similar more rapid rate than observed in the first two cycles of DSS exposure. No differences in weight loss between the DSS-treated IL-25−/− and WT mice were detected during the third cycle of DSS exposure, and the total clinical scores were similar at day 49 (Figure 2B). At euthanasia, both IL-25−/− and WT mice treated with DSS had a similar shortening of colon length (Figure 2C), and microscopic examination showed complete loss of crypts as well as extensive inflammatory cell infiltration in the muscularis mucosa, submucosa, and muscularis externa (Figure 2D). Dramatic and similar smooth muscle hyperplasia/hypertrophy was also evident in both IL-25−/− and WT mice. These results are consistent with the notion that mice genetically deficient in IL-25 are only partially protected from DSS-induced chronic colitis.Figure 2

Bottom Line: Several previous studies reported inconsistent results on the role of exogenous IL-25 in development of colonic inflammation and none were performed in animals with a genetic deletion of IL-25.Finally, stimulation of T84 colonic epithelial cells with IL-25 up-regulated the expression of IL-33 and several pro-inflammatory cytokines.The present study suggests that IL-25 may contribute to the pathogenesis of inflammatory bowel disease in at least a subgroup of patients.

View Article: PubMed Central - PubMed

Affiliation: Departments of Radiation Oncology and Medicine, University of Maryland School of Medicine, 10 S. Pine Street, MSTF, Room 7-00D, Baltimore, MD 21201 USA ; Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006 China.

ABSTRACT

Background: IL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote type 2 while suppressing Th1 and Th17 responses. Several previous studies reported inconsistent results on the role of exogenous IL-25 in development of colonic inflammation and none were performed in animals with a genetic deletion of IL-25. We investigated the contribution of endogenous IL-25 to DSS-induced colitis using mice deficient in IL-25.

Results: Mice were exposed to DSS in drinking water ad libitum either for seven days (acute) or for three cycles of seven days with DSS followed by 14 days without DSS (chronic) to induce colitis, respectively. The loss of body weight, appearance of diarrhea and bloody stools, and shortening of colon length were significantly less pronounced in IL-25(-/-) mice compared to WT mice after exposure to acute DSS. Histological examination showed that DSS-treated IL-25(-/-) mice had only mild inflammation in the colon, while severe inflammation developed in DSS-treated WT mice. A significant up-regulation of IL-33 was observed in acute DSS-treated WT but not in the IL-25(-/-) mice. There was significantly lower expression of pro-inflammatory cytokines in the colon of acute DSS-treated IL-25(-/-) compared to WT mice. IL-25(-/-) mice were also partially protected from chronic DSS challenge especially during the first 2 cycles of DSS exposure. In contrast to IL-25(-/-) mice, IL-13(-/-) mice were more susceptible to DSS-induced colitis. Finally, stimulation of T84 colonic epithelial cells with IL-25 up-regulated the expression of IL-33 and several pro-inflammatory cytokines.

Conclusions: These data indicate that endogenous IL-25 acts as a pro-inflammatory factor in DSS-induced colitis, which is unlikely to be mediated by IL-13 but possibly the induction of IL-33 and other pro-inflammatory mediators from colonic epithelial cells. The present study suggests that IL-25 may contribute to the pathogenesis of inflammatory bowel disease in at least a subgroup of patients.

No MeSH data available.


Related in: MedlinePlus