Abstract:ObjectiveWe evaluated different dose effects of rIL-25 on acute ulcerative colitis.Materials and methodsMice were fed 2.5% dextran sulfate sodium (DSS) for 5 days while infused i.p. with repeated doses of rIL-25 (0.2, 0.4 and 0.8 μg) in PBS or PBS only after every 24 h at the same time as the start of the DSS exposure. Clinical, macroscopical and microscopical assessment of colitis severity with survival study was performed. Colonic IL-25 expression and production of IFN-γ, IL-10 and IL-4 was also analyzed.Res… Show more
“…Histological evaluation of H&E-stained tissue sections of colon showed that IL-25 −/− mice treated with DSS had lower HAI with only mild inflammation, while extensive inflammation developed in DSS-treated WT mice based on the extent of focal crypt lesions, loss of goblet cells, and infiltration of inflammatory cells (Figure 1 D & E). These results suggest that endogenous IL-25 plays a pro-inflammatory role in DSS-induced acute colitis, rather than an anti-inflammatory role proposed by a previous study using exogenous IL-25 [ 19 , 20 ]. Figure 1 Mice genetically deficient in IL-25 are protected from acute dextran sulfate sodium (DSS)-induced colitis.…”
Section: Resultsmentioning
confidence: 47%
“…Our results are contrary to a previous study showing that exogenous IL-25 had an inhibitory effect on the development of DSS colitis [ 19 ]. The reason for the inconsistency is not known, but a follow-up study from the same group indicated that only high doses (0.8 μg daily) of exogenous IL-25 protected, while low doses (0.2 μg daily) of IL-25 aggravated the DSS-induced colitis [ 20 ]. We made attempts to replicate those studies with exogenous IL-25 [ 19 , 20 ], but the results were inconclusive since daily IL-25 administration significantly reduced water/DSS consumption of the mice, which altered the outcome (Zhao A, et al unpublished results).…”
Section: Discussionmentioning
confidence: 99%
“…The reason for the inconsistency is not known, but a follow-up study from the same group indicated that only high doses (0.8 μg daily) of exogenous IL-25 protected, while low doses (0.2 μg daily) of IL-25 aggravated the DSS-induced colitis [ 20 ]. We made attempts to replicate those studies with exogenous IL-25 [ 19 , 20 ], but the results were inconclusive since daily IL-25 administration significantly reduced water/DSS consumption of the mice, which altered the outcome (Zhao A, et al unpublished results). It is possible that the decrease in DSS consumption actually accounted for the protective effects of exogenous IL-25 observed in the previous studies [ 19 , 20 ].…”
Section: Discussionmentioning
confidence: 99%
“…We made attempts to replicate those studies with exogenous IL-25 [ 19 , 20 ], but the results were inconclusive since daily IL-25 administration significantly reduced water/DSS consumption of the mice, which altered the outcome (Zhao A, et al unpublished results). It is possible that the decrease in DSS consumption actually accounted for the protective effects of exogenous IL-25 observed in the previous studies [ 19 , 20 ]. While none of the previous studies were performed to understand the role of endogenous IL-25 in mouse models of colitis, our results demonstrate that constitutive IL-25 is a pro-inflammatory factor for the development of DSS colitis in mice and, therefore, may contribute to colonic inflammation in at least a subgroup of patients with IBD.…”
BackgroundIL-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.ResultsMice 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.ConclusionsThese 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.
“…Histological evaluation of H&E-stained tissue sections of colon showed that IL-25 −/− mice treated with DSS had lower HAI with only mild inflammation, while extensive inflammation developed in DSS-treated WT mice based on the extent of focal crypt lesions, loss of goblet cells, and infiltration of inflammatory cells (Figure 1 D & E). These results suggest that endogenous IL-25 plays a pro-inflammatory role in DSS-induced acute colitis, rather than an anti-inflammatory role proposed by a previous study using exogenous IL-25 [ 19 , 20 ]. Figure 1 Mice genetically deficient in IL-25 are protected from acute dextran sulfate sodium (DSS)-induced colitis.…”
Section: Resultsmentioning
confidence: 47%
“…Our results are contrary to a previous study showing that exogenous IL-25 had an inhibitory effect on the development of DSS colitis [ 19 ]. The reason for the inconsistency is not known, but a follow-up study from the same group indicated that only high doses (0.8 μg daily) of exogenous IL-25 protected, while low doses (0.2 μg daily) of IL-25 aggravated the DSS-induced colitis [ 20 ]. We made attempts to replicate those studies with exogenous IL-25 [ 19 , 20 ], but the results were inconclusive since daily IL-25 administration significantly reduced water/DSS consumption of the mice, which altered the outcome (Zhao A, et al unpublished results).…”
Section: Discussionmentioning
confidence: 99%
“…The reason for the inconsistency is not known, but a follow-up study from the same group indicated that only high doses (0.8 μg daily) of exogenous IL-25 protected, while low doses (0.2 μg daily) of IL-25 aggravated the DSS-induced colitis [ 20 ]. We made attempts to replicate those studies with exogenous IL-25 [ 19 , 20 ], but the results were inconclusive since daily IL-25 administration significantly reduced water/DSS consumption of the mice, which altered the outcome (Zhao A, et al unpublished results). It is possible that the decrease in DSS consumption actually accounted for the protective effects of exogenous IL-25 observed in the previous studies [ 19 , 20 ].…”
Section: Discussionmentioning
confidence: 99%
“…We made attempts to replicate those studies with exogenous IL-25 [ 19 , 20 ], but the results were inconclusive since daily IL-25 administration significantly reduced water/DSS consumption of the mice, which altered the outcome (Zhao A, et al unpublished results). It is possible that the decrease in DSS consumption actually accounted for the protective effects of exogenous IL-25 observed in the previous studies [ 19 , 20 ]. While none of the previous studies were performed to understand the role of endogenous IL-25 in mouse models of colitis, our results demonstrate that constitutive IL-25 is a pro-inflammatory factor for the development of DSS colitis in mice and, therefore, may contribute to colonic inflammation in at least a subgroup of patients with IBD.…”
BackgroundIL-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.ResultsMice 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.ConclusionsThese 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.
“…Mchenga et al . found that, in dextran sulfate sodium-induced colitis, low dose (0.2 mg) aggravated, while high dose (0.8 mg) significantly attenuated colitis22. This phenomenon was also observed on Granulocyte macrophage colony stimulating factor (GM-CSF).…”
IL-25, a new member of the IL-17 cytokine family, is involved in type 2 immunity initiation and has been associated with the pathogenesis of rheumatoid arthritis (RA). However, its exact role remains unclear. Here, we aimed to analyse IL-25 expression in the serum and synovial fluid of RA patients and evaluated the correlations between serum IL-25 levels, clinical and laboratory values and inflammation cytokines. Additionally, we investigated whether IL-25 can suppress Th1/Th17 responses involved in RA pathogenesis. We further determined whether IL-25 can alleviate collagen-induced arthritis (CIA) development in mice and the underlying mechanisms using in vitro and in vivo experiments. Our results showed that IL-25 was upregulated in the serum and synovial fluid of RA patients. Increased serum IL-25 levels were associated with disease severity and inflammatory response in RA patients. Furthermore, IL-25 inhibited CD4+ T-cell activation and differentiation into Th17 cells, without affecting Th1 cells in human RA and CIA models. Administration of IL-25 could attenuate CIA development by Th17 suppression in an IL-13-dependent manner. Our findings indicate that IL-25 plays a potent immunosuppressive role in the pathogenesis of RA and CIA by downregulating Th17 cell response, and thus, may be a potential therapeutic agent for RA.
Colorectal cancer (CRC) is one of the most common cancers in both genders. Even though interleukin (IL)-17A was shown to play an important role in intestinal tumourigenesis and CRC, other IL-17 family members were not studied well. We therefore studied the expression of IL-17 cytokine family members in CRC. Ten healthy colons and ten CRC mucosa were immunostained for IL-17B, IL-17C, IL-17E, and IL-17F, and their receptors IL-17RA, IL-17RB, and IL-17RC. Double immunofluorescence staining of the CRC mucosa was done for IL-17B with markers of neutrophils, endothelial cells, macrophages, T cells, mast cells, or fibroblasts. While IL-17B was increased in CRC with a strong presence both in the epithelial and stromal compartments, IL-17C showed different expression depending on the grade of differentiation and IL-17E remained unchanged. In contrast, IL-17F was decreased in CRC compared to healthy control. Colon epithelial cells stained positive for IL-17RA, IL-17RB, and IL-17RC in both healthy control and CRC. Neutrophils were the main source of IL-17B in the stroma. family members demonstrated distinct expression patterns in CRC, suggesting a differential role exerted by each member in colon carcinogenesis.
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