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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

IL-5 gene-deficient and CD1d gene-deficient mice were protected from eosinophilic and mast cell inflammation following rIL-18-induced intranasal exposureThe induction of EoE is examined in wild type, IL-5 gene-deficient and CD1d genes-deficient mice following repeated inoculations of intranasal saline or rIL-18 treatment as described in the method section. Morphometric analysis of absolute numbers of eosinophils and mast cells in wild type mice and IL-5 gene-deficient mice is shown (A, B). The number of eosinophils and mast cells in wild-type mice and CD1d gene-deficient mice is shown (C, D). The data are expressed as the means ± SD pooled from 3 experiments (4-mice/group/treatment/experiments; total mice=12/group).
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Figure 6: IL-5 gene-deficient and CD1d gene-deficient mice were protected from eosinophilic and mast cell inflammation following rIL-18-induced intranasal exposureThe induction of EoE is examined in wild type, IL-5 gene-deficient and CD1d genes-deficient mice following repeated inoculations of intranasal saline or rIL-18 treatment as described in the method section. Morphometric analysis of absolute numbers of eosinophils and mast cells in wild type mice and IL-5 gene-deficient mice is shown (A, B). The number of eosinophils and mast cells in wild-type mice and CD1d gene-deficient mice is shown (C, D). The data are expressed as the means ± SD pooled from 3 experiments (4-mice/group/treatment/experiments; total mice=12/group).

Mentions: IL-5 and iNKT cells have been shown to be critical in promoting experimental EoE, as IL-18-activated iNKT cells produce eosinophil activating cytokines, including IL-5, in an antigen-independent manner.9, 10 Most recently, we have shown that a non-immortalised human iNKT cell line24 exposed to IL-18 in vitro produces IL-5 and IL-13. 23 Therefore, to understand the mechanism of IL-18-induced experimental EoE, wild-type, IL-5-deficient and CD1d-deficient mice were given intranasal saline or IL-18 (5 doses of 5 μg) on alternate days, and oesophageal eosinophilia and mast cells were examined in the oesophagus as described earlier.2, 25 Both IL-5-deficient and iNKT-deficient mice were protected from IL-18-induced oesophageal eosinophilia compared with wild-type mice, which developed significant oesophageal eosinophilia (Figure 6 A, C). However, a comparable number of oesophageal mast cells was found in both IL-5- and CD1d-deficient mice compared with wild type (Figure 6 B, D). The data are expressed as the means ± SD, mice = 12/group, p<0.001.


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)

IL-5 gene-deficient and CD1d gene-deficient mice were protected from eosinophilic and mast cell inflammation following rIL-18-induced intranasal exposureThe induction of EoE is examined in wild type, IL-5 gene-deficient and CD1d genes-deficient mice following repeated inoculations of intranasal saline or rIL-18 treatment as described in the method section. Morphometric analysis of absolute numbers of eosinophils and mast cells in wild type mice and IL-5 gene-deficient mice is shown (A, B). The number of eosinophils and mast cells in wild-type mice and CD1d gene-deficient mice is shown (C, D). The data are expressed as the means ± SD pooled from 3 experiments (4-mice/group/treatment/experiments; total mice=12/group).
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Related In: Results  -  Collection

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Figure 6: IL-5 gene-deficient and CD1d gene-deficient mice were protected from eosinophilic and mast cell inflammation following rIL-18-induced intranasal exposureThe induction of EoE is examined in wild type, IL-5 gene-deficient and CD1d genes-deficient mice following repeated inoculations of intranasal saline or rIL-18 treatment as described in the method section. Morphometric analysis of absolute numbers of eosinophils and mast cells in wild type mice and IL-5 gene-deficient mice is shown (A, B). The number of eosinophils and mast cells in wild-type mice and CD1d gene-deficient mice is shown (C, D). The data are expressed as the means ± SD pooled from 3 experiments (4-mice/group/treatment/experiments; total mice=12/group).
Mentions: IL-5 and iNKT cells have been shown to be critical in promoting experimental EoE, as IL-18-activated iNKT cells produce eosinophil activating cytokines, including IL-5, in an antigen-independent manner.9, 10 Most recently, we have shown that a non-immortalised human iNKT cell line24 exposed to IL-18 in vitro produces IL-5 and IL-13. 23 Therefore, to understand the mechanism of IL-18-induced experimental EoE, wild-type, IL-5-deficient and CD1d-deficient mice were given intranasal saline or IL-18 (5 doses of 5 μg) on alternate days, and oesophageal eosinophilia and mast cells were examined in the oesophagus as described earlier.2, 25 Both IL-5-deficient and iNKT-deficient mice were protected from IL-18-induced oesophageal eosinophilia compared with wild-type mice, which developed significant oesophageal eosinophilia (Figure 6 A, C). However, a comparable number of oesophageal mast cells was found in both IL-5- and CD1d-deficient mice compared with wild type (Figure 6 B, D). The data are expressed as the means ± SD, mice = 12/group, p<0.001.

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