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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-18 levels in allergen-induced experimental eosinophilic oesophagitisThe aeroallergen (Aspergillus extract) and food allergen (peanut extract) challenge protocol of experimental EoE is shown (A, B). The protocol details are provided in the method section. The blood IL-18 protein levels following Aspergillus extract (C) and peanut extract (D) challenge are shown in mice. IL-18Rα mRNA levels in the oesophagus of Aspergillus extract (E) and peanut extract (F) challenged are shown in mice. A flowcytometer analysis was performed to measure IL-18Rα expression in CD4+ iNKT cells is shown in the oesophagus of Aspergillus-induced mouse model of EoE (G-I). 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 1: IL-18 levels in allergen-induced experimental eosinophilic oesophagitisThe aeroallergen (Aspergillus extract) and food allergen (peanut extract) challenge protocol of experimental EoE is shown (A, B). The protocol details are provided in the method section. The blood IL-18 protein levels following Aspergillus extract (C) and peanut extract (D) challenge are shown in mice. IL-18Rα mRNA levels in the oesophagus of Aspergillus extract (E) and peanut extract (F) challenged are shown in mice. A flowcytometer analysis was performed to measure IL-18Rα expression in CD4+ iNKT cells is shown in the oesophagus of Aspergillus-induced mouse model of EoE (G-I). The data are expressed as the means ± SD pooled from 3 experiments, (4-mice/group/treatment/experiments; total mice=12/group).

Mentions: Our previously reported microarray data showed increased IL-18R transcript levels in EoE patients compared with normal individuals. 8 Therefore, we sought to understand the role of IL-18 in EoE pathogenesis. Accordingly, we first determined blood IL-18 and oesophageal IL-18R levels in a murine model of EoE. Experimental EoE was induced in mice with an aeroallergen (Aspergillus) or food allergen (peanut) as per the protocol shown in Figure 1 A, B. ELISA analysis of blood from Aspergillus- or peanut-challenged mice showed highly elevated IL-18 protein levels (Figure 1 C, D; n=3 experiments); in the saline treated mice, IL-18 protein was non-detectable. Furthermore, quantitative PCR analyses showed enhanced expression of IL-18R in the oesophagus (Figure 1 E, F; n=3 experiments) of both allergen challenged mice compared with the saline control. Notably, our earlier analysis indicated that iNKT cells are induced in the oesophagus following EoE induction; therefore, our interest was whether iNKT cells are the source of IL-18R mRNA. We next tested the hypothesis that iNKT cells are the source of IL-18 transcripts in the oesophagus. Accordingly, we analysed oesophageal iNKT cells for the expression of IL-18R. Total oesophageal cells were analysed for IL-18 expression by iNKT cells in the mouse model of EoE. Herein, we demonstrate that iNKT cells express IL-18R in the oesophagus following Aspergillus-induced experimental EoE (Figure 1, G-I; n=3 experiment).


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-18 levels in allergen-induced experimental eosinophilic oesophagitisThe aeroallergen (Aspergillus extract) and food allergen (peanut extract) challenge protocol of experimental EoE is shown (A, B). The protocol details are provided in the method section. The blood IL-18 protein levels following Aspergillus extract (C) and peanut extract (D) challenge are shown in mice. IL-18Rα mRNA levels in the oesophagus of Aspergillus extract (E) and peanut extract (F) challenged are shown in mice. A flowcytometer analysis was performed to measure IL-18Rα expression in CD4+ iNKT cells is shown in the oesophagus of Aspergillus-induced mouse model of EoE (G-I). The data are expressed as the means ± SD pooled from 3 experiments, (4-mice/group/treatment/experiments; total mice=12/group).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: IL-18 levels in allergen-induced experimental eosinophilic oesophagitisThe aeroallergen (Aspergillus extract) and food allergen (peanut extract) challenge protocol of experimental EoE is shown (A, B). The protocol details are provided in the method section. The blood IL-18 protein levels following Aspergillus extract (C) and peanut extract (D) challenge are shown in mice. IL-18Rα mRNA levels in the oesophagus of Aspergillus extract (E) and peanut extract (F) challenged are shown in mice. A flowcytometer analysis was performed to measure IL-18Rα expression in CD4+ iNKT cells is shown in the oesophagus of Aspergillus-induced mouse model of EoE (G-I). The data are expressed as the means ± SD pooled from 3 experiments, (4-mice/group/treatment/experiments; total mice=12/group).
Mentions: Our previously reported microarray data showed increased IL-18R transcript levels in EoE patients compared with normal individuals. 8 Therefore, we sought to understand the role of IL-18 in EoE pathogenesis. Accordingly, we first determined blood IL-18 and oesophageal IL-18R levels in a murine model of EoE. Experimental EoE was induced in mice with an aeroallergen (Aspergillus) or food allergen (peanut) as per the protocol shown in Figure 1 A, B. ELISA analysis of blood from Aspergillus- or peanut-challenged mice showed highly elevated IL-18 protein levels (Figure 1 C, D; n=3 experiments); in the saline treated mice, IL-18 protein was non-detectable. Furthermore, quantitative PCR analyses showed enhanced expression of IL-18R in the oesophagus (Figure 1 E, F; n=3 experiments) of both allergen challenged mice compared with the saline control. Notably, our earlier analysis indicated that iNKT cells are induced in the oesophagus following EoE induction; therefore, our interest was whether iNKT cells are the source of IL-18R mRNA. We next tested the hypothesis that iNKT cells are the source of IL-18 transcripts in the oesophagus. Accordingly, we analysed oesophageal iNKT cells for the expression of IL-18R. Total oesophageal cells were analysed for IL-18 expression by iNKT cells in the mouse model of EoE. Herein, we demonstrate that iNKT cells express IL-18R in the oesophagus following Aspergillus-induced experimental EoE (Figure 1, G-I; n=3 experiment).

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