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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-13 are more susceptible to acute dextran sulfate sodium (DSS)-induced colitis. Mice were given 3.0% DSS in drinking water for 7 days and euthanized at day 8. (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); (E) Histological activity index from a total score of epithelial damage (0–4) and immune cell infiltration (0–4); (F) In situ cytokine production in the colon by ELISA. Data are mean ± SEM and are representatives of two independent experiments with five mice per group. *P < 0.05 versus the respective VEH; ϕ P < 0.05 versus respective WT.
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Fig4: Mice genetically deficient in IL-13 are more susceptible to acute dextran sulfate sodium (DSS)-induced colitis. Mice were given 3.0% DSS in drinking water for 7 days and euthanized at day 8. (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); (E) Histological activity index from a total score of epithelial damage (0–4) and immune cell infiltration (0–4); (F) In situ cytokine production in the colon by ELISA. Data are mean ± SEM and are representatives of two independent experiments with five mice per group. *P < 0.05 versus the respective VEH; ϕ P < 0.05 versus respective WT.

Mentions: IL-13 is one of the major downstream effector molecules that mediates the biological activities of IL-25 [23]. To address whether resistance to DSS-induced colitis conferred by IL-25 deficiency was attributable to a defect in IL-13 expression, we exposed IL-13−/− mice to DSS for seven days. When compared with the age- and sex-matched WT mice, IL-13−/− mice lost significantly more body weight (Figure 4A) and developed exacerbated disease activity (Figure 4B) during the course of acute DSS exposure, contrary to that observed in IL-25−/− mice. At euthanasia, the extent of colon shortening was worse in DSS-treated IL-13−/− mice than in WT mice (Figure 4C). In addition, the colons from DSS-treated IL-13−/− mice had significantly higher HAI than that of DSS-treated WT mice, evidenced by the presence of severe denudation of the surface epithelium, extensive loss of crypts and separation of the crypt base from the muscularis mucosa, as well as enhanced inflammatory cell infiltration in the submucosa (Figure 4D & E). ELISA analysis of in situ cytokine production revealed that the colons from DSS-treated IL-13−/− mice produced significantly more IL-6, TNFα, and IL-17A than that of DSS-treated WT mice (Figure 4F). Overall, these results suggest that mice deficient in IL-13 have increased susceptibility to acute DSS-induced colitis, ruling out the possibility that the decreased susceptibility to DSS-induced colitis in IL-25−/− mice is due to a lack of IL-13.Figure 4


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-13 are more susceptible to acute dextran sulfate sodium (DSS)-induced colitis. Mice were given 3.0% DSS in drinking water for 7 days and euthanized at day 8. (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); (E) Histological activity index from a total score of epithelial damage (0–4) and immune cell infiltration (0–4); (F) In situ cytokine production in the colon by ELISA. Data are mean ± SEM and are representatives of two independent experiments with five mice per group. *P < 0.05 versus the respective VEH; ϕ P < 0.05 versus respective WT.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Mice genetically deficient in IL-13 are more susceptible to acute dextran sulfate sodium (DSS)-induced colitis. Mice were given 3.0% DSS in drinking water for 7 days and euthanized at day 8. (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); (E) Histological activity index from a total score of epithelial damage (0–4) and immune cell infiltration (0–4); (F) In situ cytokine production in the colon by ELISA. Data are mean ± SEM and are representatives of two independent experiments with five mice per group. *P < 0.05 versus the respective VEH; ϕ P < 0.05 versus respective WT.
Mentions: IL-13 is one of the major downstream effector molecules that mediates the biological activities of IL-25 [23]. To address whether resistance to DSS-induced colitis conferred by IL-25 deficiency was attributable to a defect in IL-13 expression, we exposed IL-13−/− mice to DSS for seven days. When compared with the age- and sex-matched WT mice, IL-13−/− mice lost significantly more body weight (Figure 4A) and developed exacerbated disease activity (Figure 4B) during the course of acute DSS exposure, contrary to that observed in IL-25−/− mice. At euthanasia, the extent of colon shortening was worse in DSS-treated IL-13−/− mice than in WT mice (Figure 4C). In addition, the colons from DSS-treated IL-13−/− mice had significantly higher HAI than that of DSS-treated WT mice, evidenced by the presence of severe denudation of the surface epithelium, extensive loss of crypts and separation of the crypt base from the muscularis mucosa, as well as enhanced inflammatory cell infiltration in the submucosa (Figure 4D & E). ELISA analysis of in situ cytokine production revealed that the colons from DSS-treated IL-13−/− mice produced significantly more IL-6, TNFα, and IL-17A than that of DSS-treated WT mice (Figure 4F). Overall, these results suggest that mice deficient in IL-13 have increased susceptibility to acute DSS-induced colitis, ruling out the possibility that the decreased susceptibility to DSS-induced colitis in IL-25−/− mice is due to a lack of IL-13.Figure 4

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