Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University; and First Department of Internal Medicine, Kurume University, Fukuoka, Japan
Interleukin (IL)-13 induces important features of bronchial
asthma such as eosinophilic infiltration, airway hyperresponsiveness
(AHR), and mucus hypersecretion. Although glucocorticoids suppress
airway inflammation and remain the most effective therapy for
asthma, the effects of glucocorticoids on the IL-13–dependent
features are unknown. We studied the effects of dexamethasone
on eotaxin production, eosinophil accumulation, goblet cell
hyperplasia, and AHR after IL-13 administration into the airways
of mice
in vivo. MUC5AC gene expression, a marker of goblet
cell hyperplasia, was also analyzed. IL-13 alone dose dependently
induced AHR. Treatment with dexamethasone inhibited eotaxin
expression and completely abolished eosinophil accumulation,
but it did not affect AHR, MUC5AC overexpression, or goblet
cell hyperplasia induced by IL-13. The effects of tumor necrosis
factor- on IL-13–induced AHR were also examined. Tumor
necrosis factor- did not affect AHR despite marked enhancement
of eosinophil infiltration in IL-13–treated mice. These
findings suggest that glucocorticoid is not sufficient to suppress
IL-13–induced AHR or goblet cell hyperplasia and that
eotaxin expression and eosinophilic inflammation do not have
a causal relationship to the induction of AHR or goblet cell
hyperplasia by IL-13. Control of steroid-resistant features
induced by IL-13, including AHR and mucus production, may provide
new therapeutic modalities for asthma.
Key Words: airway hyperreactivity • corticosteroid • cytokine • eosinophil • goblet cell metaplasia
Bronchial asthma is a disease that is characterized by chronic
inflammation, eosinophilic infiltration, reversible airway narrowing,
airway hyperresponsiveness (AHR) to nonspecific stimuli, hyperplasia/metaplasia
of goblet cells, and subepithelial fibrosis (
1,
2). Although
the mechanisms underlying these features are complex, CD4
+ Th2
lymphocytes and their cytokine products, such as interleukin
(IL)-4, IL-5, IL-9, and IL-13, play a crucial role in generating
these abnormalities. In patients with asthma, CD4
+ T cells producing
IL-4, IL-5, and IL-13 have been identified in bronchoalveolar
lavage (BAL) and airway biopsy (
3). Animal studies have also
shown that Th2 cells induced airway eosinophilia, mucus hypersecretion,
and AHR (
4,
5).
Increased expression of IL-13 has been demonstrated in the airways of patients with asthma (6, 7). Furthermore, local administration of recombinant IL-13 to nonimmunized mice induces eosinophil influx in the airways, goblet cell hyperplasia with mucus hypersecretion, and AHR (8). Chronic overproduction of IL-13 in the airways induces epithelial eotaxin expression, pathologic changes of asthma, and AHR in mice (9). Neutralization of eotaxin reduces airway eosinophilia and AHR in a mouse model of asthma (10). In vivo blockade of IL-13 by a soluble IL-13 receptor
作者:
Atsuko Kibe, Hiromasa Inoue, Satoru Fukuyama, Kent 2007-5-14