IL-4 Is a Potent Modulator of Ion Transport in the Human Bronchial Epithelium In Vitro

Abstract

Recent data show that proinflammatory stimuli may modify significantly ion transport in the airway epithelium and therefore the properties of the airway surface fluid. We have studied the effect of IL-4, a cytokine involved in the pathogenesis of asthma, on transepithelial ion transport in the human bronchial epithelium in vitro. Incubation of polarized bronchial epithelial cells with IL-4 for 6–48 h causes a marked inhibition of the amiloride-sensitive Na+ channel as measured in short circuit current experiments. On the other hand, IL-4 evokes a 2-fold increase in the current activated by a cAMP analog, which reflects the activity of the cystic fibrosis transmembrane conductance regulator (CFTR). Similarly, IL-4 enhances the response to apical UTP, an agonist that activates Ca2+-dependent Cl− channels. These effects are mimicked by IL-13 and blocked by an antagonist of IL-4Rα. RT-PCR experiments show that IL-4 elicits a 7-fold decrease in the level of the γ amiloride-sensitive Na+ channel mRNA, one of the subunits of the amiloride-sensitive Na+ channel, and an increase in CFTR mRNA. Our data suggest that IL-4 may favor the hydration of the airway surface by decreasing Na+ absorption and increasing Cl− secretion. This could be required to fluidify the mucus, which is hypersecreted during inflammatory conditions. On the other hand, the modifications of ion transport could also affect the ion composition of airway surface fluid.

Role of STAT6 and Mast Cells in IL-4- and IL-13-Induced Alterations in Murine Intestinal Epithelial Cell Function

“…This apparent conflict may be explained by the in vivo administration of the cytokines in our study, as well as by inherent differences in the function of homogeneous intestinal epithelial cell lines vs excised intestinal mucosae with its intact neural circuitry. However, it is of interest to note that two other recent reports have shown 1) a dose-dependent decrease in the resistance of rat glomerular visceral epithelial cells in vitro in response to IL-4 or IL-13 (31), and 2) decreased Na ϩ absorption and increased Cl Ϫ secretion in vitro in response to IL-4 treatment of human bronchial epithelial cells (32). Results of these studies suggest that the effects of IL-4 and IL-13 on epithelial cell function may not be limited to the gastrointestinal tract, but rather may represent a broader mechanism of immunoregulation at epithelial cell surfaces.…”

Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

“…Indeed, even without considering the absence of effect of 6-MP on AFC, there is little evidence that the decline in AFC on Day 2 is a consequence of the immune response to the virus. Although certain proinflammatory cytokines have been shown to modulate Na ϩ transport in vitro or in vivo (37)(38)(39)(40), analysis of BAL fluid from RSV-infected mice reveals no temporal correlation between pulmonary inflammation and inhibition of AFC. For example, whereas IFN-␥ has been shown to inhibit Na ϩ transport in vitro (38), no IFN-␥ is detectable in BAL fluid on Day 2, when AFC is most depressed, and AFC values are normal on Day 6, when BAL IFN-␥ levels are highest.…”

The pros and cons of immunomodulatory IL-10 gene therapy with recombinant AAV in a Cftr−/−-dependent allergy mouse model

“…In fact, CF patients were recently characterized to have excessive IL-4 and IL-13 production, which may have a direct influence in the prevalence of allergic asthma in this population. [25][26][27][28] Approximately 5.5% of American children are afflicted with asthma. Although this represents a very high prevalence, asthma is much more common in children with CF, where the rate of bronchial hyper-responsiveness approaches 50%, and up to 10-15% may experience a hyper-IgE asthma variant known as allergic bronchopulmonary aspergillosis (ABPA).…”