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. 2017 Sep 15;9(9):4137-4148.
eCollection 2017.

The role of IL-25 in the reduction of oxidative stress and the apoptosis of airway epithelial cells with specific immunotherapy in an asthma mouse model

Xiefang Yuan  1 , Eryi Wang  2 , Xiaojun Xiao  2 , Junyi Wang  3 , Xiaomeng Yang  2 , Pingchang Yang  2 , Guoping Li  1   3 , Zhigang Liu  2
Affiliations

The role of IL-25 in the reduction of oxidative stress and the apoptosis of airway epithelial cells with specific immunotherapy in an asthma mouse model

Xiefang Yuan et al. Am J Transl Res. .

Abstract

Oxidative stress and cell apoptosis play important roles in the pathogenesis of asthma. Specific immunotherapy (SIT) is the only curative approach for asthma and is effective at decreasing asthmatic oxidation and cell apoptosis, but the mechanisms remain unclear. In this study, by using in vivo and in vitro models, we indirectly demonstrated that SIT alleviated the apoptosis and oxidative stress of bronchial epithelial cells in an asthma model through regulating interleukin (IL)-25. Female BALB/c mice were used for an asthma model induced by exposure to house dust mite (HDM) extracts as allergens. Prior to the challenge, the mice were either given the SIT vaccine or N-Acetyl-L-cysteine (NAC).

Results: Compared with that in asthma models, SIT administration decreased (1) airway hyper-responsiveness; (2) the production of cytokines, including IL-4, IL-5, IL-13, and IL-25, as well as serum HDM-specific IgE and IgG1, as shown by ELISA; and (3) lipid oxidative species, such as reactive oxidative species (ROS) and malondialdehyde (MDA), in the lung tissue. Moreover, TUNEL staining showed that SIT alleviated pulmonary cell apoptosis. In vitro, flow cytometry showed that human recombinant IL-25 (rIL-25) led to increased cell apoptosis and ROS in the human epithelial cell line 16HBE in a dose and time-dependent fashion. In conclusion, in vivo, SIT reduced asthmatic Th2 cytokine levels and the production of IL-25 and alleviated oxidative stress and cell apoptosis in the lung tissue. In vitro, IL-25 increased the number of apoptotic cells and the production of ROS in16HBE cells.

Keywords: Asthma; IL-25; epithelial cells; reactive oxygen species (ROS); specific immunotherapy (SIT).

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
SIT and NAC alleviate asthmatic symptoms in a mouse model. The design of the model is shown in (A). Histology of a lung stained with H&E (B) and PAS (C) at 10× magnification. The AHR of the four groups is shown in (D). The results are representative of 3 independent experiments. The statistics of the results were performed by student t-test. *means P<0.05, **means P<0.01.
Figure 2
Figure 2
In the mouse model, compared with those in the asthma group, SIT reduces the levels of Th2 cytokines and IL-25 as well as sIgE and sIgG1 in the serum. A: The levels of IL-4 and IL-5 in serum, IL-13 in the BALF, and IL-25 in the homogenized lung tissue were measured by ELISA. B: The levels of HDM-specific IgE and IgG1 were measured by ELISA, and the value is shown as the optical density read at 450 nm (OD450). The results are representative of 3 independent experiments. The statistics of the results were performed by student t-test. *means P<0.05, **means P<0.01.
Figure 3
Figure 3
In the mouse model, dust mite SIT alleviates the oxidative stress of lung tissue. (A) The level of MDA in the homogenized murine lung tissue was measured. (B and C) The ROS level in the BALF was measured by flow cytometry. One of the 3 results are shown in the histogram (B) and the ratio of cells with ROS in the BALF was analyzed (C). (D) Frozen lung section stained by the fluorescent ROS antibody observed at 10× magnification. The results are representative of 3 independent experiments. The statistics of the results were performed by student t-test. *means P<0.05, **means P<0.01.
Figure 4
Figure 4
Dust mite SIT reduces apoptosis in pulmonary tissue. In vivo, SIT reduced lung apoptosis, and in vitro, IL-25 increased the apoptosis and ROS of 16HBE cells in a time and dose-dependent fashion. A: In the mouse model, the apoptosis of lung tissue was shown with TUNEL staining observed at 10× magnification. B and C: In vitro, apoptosis of 16HBE cells was shown with Annexin V-FITC/PI detection after exposure to various doses of human rIL-25 for different durations (A: control for 12 h; B: 0.1 mg/ml for 12 h; C: 0.1 mg/ml for 24 h; D: control for 24 h; E: 1 mg/ml for 12 h; F: 1 mg/ml for 24 h). D: The levels of ROS in 16HBE cells of the above groups were also tested using flow cytometry. The results are shown as the fluorescence intensity and are representative of 3 independent experiments. The statistics of the results were performed by student t-test. *means P<0.05, **means P<0.01.
Figure 5
Figure 5
Dust mite SIT upregulates the number of Tregs in the spleen. The spleen from mouse models were homogenized, and the percentage of Tregs (CD4+CD25+Foxp3+) in CD4+T cells was tested by flow cytometry; the results showed (A) the representative and (B) the analysis of 3 independent experiments. The statistics of the results were performed by student t-test. **means P<0.01.
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