Abrogation of bronchial eosinophilic inflammation and airway hyperreactivity in signal transducers and activators of transcription (STAT)6-deficient mice

Abstract

Signal transducers and activators of transcription 6 (STAT6) is essential for interleukin 4-mediated responses, including class switching to IgE and induction of type 2 T helper cells. To investigate the role of STAT6 in allergic asthma in vivo, we developed a murine model of allergen-induced airway inflammation. Repeated exposure of actively immunized C57BL/6 mice to ovalbumin (OVA) aerosol increased the level of serum IgE, the number of eosinophils in bronchoalveolar lavage (BAL) fluid, and airway reactivity. Histological analysis revealed peribronchial inflammation with pulmonary eosinophilia in OVA-treated mice. In STAT6-deficient (STAT6-/-) C57BL/6 mice treated in the same fashion, there were no eosinophilia in BAL and significantly less peribronchial inflammation than in wild-type mice. Moreover STAT6-/- mice had much less airway reactivity than wild-type mice. These findings suggest that STAT6 plays a crucial role in the pathogenesis of allergen-induced airway inflammation.

Figure 1

Changes in serum concentrations of IgE and IgM induced by OVA treatment. The columns represent the concentration of serum IgE (a) and IgM (b) in wild-type and STAT6^−/− mice after treatment with (OVA) or without (Control) OVA. Results shown are from a single experiment representative of three separate experiments. N.D., not detectable (<10 ng/ml).

Figure 2

Effect of STAT6 deficiency on total BAL cell number and cellular distribution of BAL fluid. BAL fluid was obtained from wild-type and STAT6^−/− mice after treatment with (OVA) or without (Control) OVA. The columns represent the absolute numbers of total BAL cells, eosinophils, neutrophils, macrophages, and other cells (mostly lymphocytes) per animal. Results shown are from a single experiment representative of three separate experiments.

Figure 3

Microscopic examination of lung tissues from wild-type and STAT6^−/− mice. Lung preparations from both wild-type and STAT6^−/− mice treated with or without OVA were stained with hematoxylin-eosin. Photomicrographs of these preparations were evaluated infiltration of eosinophils and other lymphocytes in bronchial mucosa and perivascular sheaths in lung. Noticeable cell accumulation of eosinophils appeared in lungs from OVA-treated wild-type mice (A). In contrast, the inflammatory cells were not shown in lungs from OVA-treated STAT6^−/− mice (B). The lungs taken from untreated wild-type mice represent normal lung histology (C). Original magnification: 200.

Figure 4

Effect of STAT6 deficiency on airway reactivity in OVA-treated mice. Airway reactivity assessed by measurement of RL after intravenous Ach challenge in wild-type mice (circles) and STAT6^−/− mice (squares) treated with (closed symbols) or without (open symbols) OVA. Only in wild-type mice, OVA treatment significantly increased airway reactivity compared with that in the untreated group (*P <0.05). Results shown are from a single experiment representative of three separate experiments.