Interleukin-9 Induces Goblet Cell Hyperplasia during Repair of Human Airway Epithelia

Abstract

Asthma is characterized by airway inflammation, smooth muscle hyperreactivity, and airway remodeling with excessive mucus production. The effect cytokines like interleukin (IL)-9 have on airway epithelia has been addressed using murine models of asthma, as well as transgenic and knockout mice. Though highly informative, differences exist between mouse and human airway epithelia, including cellular composition (e.g., Clara cells) and stem cell/plasticity capabilities. Therefore, to address cytokine effects on human airway epithelia, we have used a primary model system to ask whether IL-9 can alter cell fates of human airway epithelia. Here, we show that IL-9 has little effect on fully differentiated ciliated human airway epithelia. However, in the setting of airway injury repair, IL-9 results in goblet cell hyperplasia. A similar response was observed when the epithelium was exposed to IL-9 before it became fully differentiated. Moreover, exposure to IL-9 resulted in increased lysozyme and mucus production by the epithelia. Thus, a combination of IL-9 and mechanical injury can explain, in part, goblet cell hyperplasia that is evident in the lungs of individuals with asthma. These data suggest that interventions that limit airway epithelial damage, block IL-9, or modulate the repair process should result in decreased airway remodeling and prevent the chronic manifestations of this disease.

Sex-specific effect of IL9 polymorphisms on lung function and polysensitization

“…18,19 In humans, IL9 was found to influence chemokine release from bronchial epithelial cell 20,21 and airway smooth muscle, 22 and has also been shown to induce goblet cell hyperplasia during repair of human airway epithelia. 23 This pleiotropic effect of IL9 is in agreement with our findings. To our knowledge, no association has been reported between IL9 polymorphisms and asthma or asthma related-phenotypes except once, wherein a weak association was found between IL9 variants and atopic asthma defined by positive-specific IgE against Der p (or Der f) and house dust.…”

Effect of TH2 cytokines and interferon gamma on beat frequency of human respiratory cilia

“…Treatment with substances targeting IL-5 reduces exacerbation rate and sputum eosinophilia and increases the quality of life in clinical trials with patients having refractory eosinophilic asthma (34). IL-9 has effects on ciliated cell differentiation and mucus hypersecretion (16,35,36). Although IL-5 and IL-9 are relevant cytokines in asthma pathophysiology their influence on CBF is not yet known.…”

Regulation of Airway Mucin Gene Expression

“…IL-9's ability to directly induce MUC5AC gene expression on airway epithelial cells is controversial (92,97). Under one scenario, IL-9's ability to directly induce mucous cells in culture may require a coexisting degree of injury and repair (98). IL-9 may have some role in inducing MUC5AC expression, although its requirement in mucous cell differentiation in the mouse is not absolute (99).…”