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Allergen-induced interleukin-18 promotes experimental eosinophilic oesophagitis in mice.

Dutt P, Shukla JS, Ventateshaiah SU, Mariswamy SJ, Mattner J, Shukla A, Mishra A - Immunol. Cell Biol. (2015)

Bottom Line: Elevated levels of interleukin (IL)-18 have been reported in a number of allergic diseases.We recently reported that IL-18 in the blood and IL-18Rα mRNA in the oesophagus are induced during human eosinophilic oesophagitis (EoE).Intranasal delivery of rIL-18 induced both mast cells and eosinophilic inflammation in the oesophagus in a time- and dose-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Section of Department of Medicine, Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA.

ABSTRACT
Elevated levels of interleukin (IL)-18 have been reported in a number of allergic diseases. We recently reported that IL-18 in the blood and IL-18Rα mRNA in the oesophagus are induced during human eosinophilic oesophagitis (EoE). Additionally, we earlier showed that invariant natural killer T (iNKT) cells are critical to EoE pathogenesis; however, the mechanism of iNKT cell activation in EoE is not well understood. Therefore, the current study focused on the hypothesis that allergen-induced IL-18 may have an important role in iNKT cell-mediated EoE pathogenesis. We first validated the human EoE findings of IL-18 in experimental EoE by examining blood levels of IL-18 and oesophageal IL-18Rα mRNA levels in aeroallergen- and food allergen-induced experimental mouse models of EoE. We demonstrate that blood IL-18 protein and oesophageal IL-18Rα mRNA are induced in the mouse model of EoE and that IL-18Rα is expressed by iNKT cells in the oesophagus. Intranasal delivery of rIL-18 induced both mast cells and eosinophilic inflammation in the oesophagus in a time- and dose-dependent manner. To establish the significance of IL-18 in EoE pathogenesis, we examined DOX-inducible rtTA-CC10-IL-18 bitransgenic mice that induce IL-18 protein expression in the oesophagus. Our analysis indicated that induction of IL-18 in these mice resulted in the development of many of the characteristics of EoE, including oesophageal intraepithelial eosinophilia, increased mast cells, oesophageal remodelling and fibrosis. The current study provides evidence that IL-18 may induce iNKT cell activation to release the eosinophil-activating cytokine IL-5, as IL-5-deficient mice and iNKT cell-deficient (CD1d ) mice do not induce EoE in response to intranasal IL-18 challenge. Taken together, these findings provide evidence that allergen-induced IL-18 has a significant role in promoting IL-5- and iNKT-dependent EoE pathogenesis.

No MeSH data available.


Related in: MedlinePlus

Intranasal rIL-18 promotes dose-dependent oesophageal eosinophilic and mast cell inflammation in miceThe levels of anti-MBP immunostained eosinophils (A) and chloroacetate stained mast cells (B) in the oesophagus of rIL-18 challenged mice 18-20 hours after each dose and concentrations were quantitated as described in the method section and is shown (A, B). The data show the means ± SD pooled from 8 mice/dose/treatments. The statistical significance of each dose of rIL-18 compared with saline is indicated as *p< 0.05, **p<0.01, ***p<0.001.
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Figure 2: Intranasal rIL-18 promotes dose-dependent oesophageal eosinophilic and mast cell inflammation in miceThe levels of anti-MBP immunostained eosinophils (A) and chloroacetate stained mast cells (B) in the oesophagus of rIL-18 challenged mice 18-20 hours after each dose and concentrations were quantitated as described in the method section and is shown (A, B). The data show the means ± SD pooled from 8 mice/dose/treatments. The statistical significance of each dose of rIL-18 compared with saline is indicated as *p< 0.05, **p<0.01, ***p<0.001.

Mentions: We next tested the hypothesis that IL-18 intranasal delivery promotes oesophageal eosinophilia in mice. Accordingly, mice were intranasally challenged with 5 doses of IL-18 on alternate days using the techniques established to induce experimental EoE.26, 27, 31 Mice that received 1-5 doses of recombinant (r) IL-18 or saline on alternate days developed oesophageal eosinophilia 24 hours after each administration of IL-18 at two different doses (5 and 10 μg). In fact, the mice developed detectable oesophageal eosinophilia even after one treatment, and the severity increased with subsequent treatments before reaching a plateau between the fourth and fifth dose. Control mice treated with intranasal saline did not have significant levels of oesophageal eosinophils (Figure 2 A). As expected, IL-18 intranasal delivery also induced pulmonary eosinophilia in the same mice (data not shown). By contrast, intranasal delivery of IL-18 had no effect on eosinophil levels in the stomach (42.8 ± 28.2 vs 57.9 ± 19.4) eosinophils/mm2 in IL-18- versus saline-treated mice [mean ± SD, P = 0.8]). These results establish that intranasal delivery of IL-18 promotes concentration-dependent oesophageal eosinophilia. A number of clinical reports have indicated that mast cells are also induced in EoE. Therefore, we next examined oesophageal mast cells in mice that received 1-5 doses of 5 or 10 μg rIL-18 (or saline) on alternate days. IL-18-treated mice developed a detectable increase in oesophageal mast cells even after 1 dose, and their numbers continued to increase with subsequent doses. The control mice treated with intratracheal saline showed a baseline level of oesophageal mast cells at each dose of saline (Figure 2 B).


Allergen-induced interleukin-18 promotes experimental eosinophilic oesophagitis in mice.

Dutt P, Shukla JS, Ventateshaiah SU, Mariswamy SJ, Mattner J, Shukla A, Mishra A - Immunol. Cell Biol. (2015)

Intranasal rIL-18 promotes dose-dependent oesophageal eosinophilic and mast cell inflammation in miceThe levels of anti-MBP immunostained eosinophils (A) and chloroacetate stained mast cells (B) in the oesophagus of rIL-18 challenged mice 18-20 hours after each dose and concentrations were quantitated as described in the method section and is shown (A, B). The data show the means ± SD pooled from 8 mice/dose/treatments. The statistical significance of each dose of rIL-18 compared with saline is indicated as *p< 0.05, **p<0.01, ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581894&req=5

Figure 2: Intranasal rIL-18 promotes dose-dependent oesophageal eosinophilic and mast cell inflammation in miceThe levels of anti-MBP immunostained eosinophils (A) and chloroacetate stained mast cells (B) in the oesophagus of rIL-18 challenged mice 18-20 hours after each dose and concentrations were quantitated as described in the method section and is shown (A, B). The data show the means ± SD pooled from 8 mice/dose/treatments. The statistical significance of each dose of rIL-18 compared with saline is indicated as *p< 0.05, **p<0.01, ***p<0.001.
Mentions: We next tested the hypothesis that IL-18 intranasal delivery promotes oesophageal eosinophilia in mice. Accordingly, mice were intranasally challenged with 5 doses of IL-18 on alternate days using the techniques established to induce experimental EoE.26, 27, 31 Mice that received 1-5 doses of recombinant (r) IL-18 or saline on alternate days developed oesophageal eosinophilia 24 hours after each administration of IL-18 at two different doses (5 and 10 μg). In fact, the mice developed detectable oesophageal eosinophilia even after one treatment, and the severity increased with subsequent treatments before reaching a plateau between the fourth and fifth dose. Control mice treated with intranasal saline did not have significant levels of oesophageal eosinophils (Figure 2 A). As expected, IL-18 intranasal delivery also induced pulmonary eosinophilia in the same mice (data not shown). By contrast, intranasal delivery of IL-18 had no effect on eosinophil levels in the stomach (42.8 ± 28.2 vs 57.9 ± 19.4) eosinophils/mm2 in IL-18- versus saline-treated mice [mean ± SD, P = 0.8]). These results establish that intranasal delivery of IL-18 promotes concentration-dependent oesophageal eosinophilia. A number of clinical reports have indicated that mast cells are also induced in EoE. Therefore, we next examined oesophageal mast cells in mice that received 1-5 doses of 5 or 10 μg rIL-18 (or saline) on alternate days. IL-18-treated mice developed a detectable increase in oesophageal mast cells even after 1 dose, and their numbers continued to increase with subsequent doses. The control mice treated with intratracheal saline showed a baseline level of oesophageal mast cells at each dose of saline (Figure 2 B).

Bottom Line: Elevated levels of interleukin (IL)-18 have been reported in a number of allergic diseases.We recently reported that IL-18 in the blood and IL-18Rα mRNA in the oesophagus are induced during human eosinophilic oesophagitis (EoE).Intranasal delivery of rIL-18 induced both mast cells and eosinophilic inflammation in the oesophagus in a time- and dose-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Section of Department of Medicine, Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA.

ABSTRACT
Elevated levels of interleukin (IL)-18 have been reported in a number of allergic diseases. We recently reported that IL-18 in the blood and IL-18Rα mRNA in the oesophagus are induced during human eosinophilic oesophagitis (EoE). Additionally, we earlier showed that invariant natural killer T (iNKT) cells are critical to EoE pathogenesis; however, the mechanism of iNKT cell activation in EoE is not well understood. Therefore, the current study focused on the hypothesis that allergen-induced IL-18 may have an important role in iNKT cell-mediated EoE pathogenesis. We first validated the human EoE findings of IL-18 in experimental EoE by examining blood levels of IL-18 and oesophageal IL-18Rα mRNA levels in aeroallergen- and food allergen-induced experimental mouse models of EoE. We demonstrate that blood IL-18 protein and oesophageal IL-18Rα mRNA are induced in the mouse model of EoE and that IL-18Rα is expressed by iNKT cells in the oesophagus. Intranasal delivery of rIL-18 induced both mast cells and eosinophilic inflammation in the oesophagus in a time- and dose-dependent manner. To establish the significance of IL-18 in EoE pathogenesis, we examined DOX-inducible rtTA-CC10-IL-18 bitransgenic mice that induce IL-18 protein expression in the oesophagus. Our analysis indicated that induction of IL-18 in these mice resulted in the development of many of the characteristics of EoE, including oesophageal intraepithelial eosinophilia, increased mast cells, oesophageal remodelling and fibrosis. The current study provides evidence that IL-18 may induce iNKT cell activation to release the eosinophil-activating cytokine IL-5, as IL-5-deficient mice and iNKT cell-deficient (CD1d ) mice do not induce EoE in response to intranasal IL-18 challenge. Taken together, these findings provide evidence that allergen-induced IL-18 has a significant role in promoting IL-5- and iNKT-dependent EoE pathogenesis.

No MeSH data available.


Related in: MedlinePlus