Interleukin‐18, IL‐18 binding protein and IL‐18 receptor expression in asthma: a hypothesis showing IL‐18 promotes epithelial cell differentiation

OBJECTIVE: In asthma, genome‐wide association studies have shown that interleukin‐18 (IL‐18) receptor 1 gene (IL‐18R1) and sputum IL‐18 are increased during exacerbations. However, the role of the IL‐18 axis in bronchial epithelial function is unclear. To investigate IL‐18, IL‐18 binding protein (BP) and IL‐18R expression in bronchial biopsies and sputum samples from patients with asthma, and to determine its functional role using in vitro bronchial epithelial cells. METHODS: The expression of IL‐18, IL‐18BP and IL‐18Rα was examined in subjects with asthma and healthy controls in bronchial biopsies by immunohistochemistry and IL‐18 and IL‐18BP release in sputum. In epithelial cells, the mRNA and protein expression of IL‐18, IL‐18BP, IL‐18Rα and IL‐18Rβ was assessed by qPCR, flow cytometry, Western blotting and immunofluorescence respectively. IL‐18 function in epithelial cells was examined by intracellular calcium, wound repair, synthetic activation and epithelial differentiation changes. RESULTS: In biopsies from subjects with asthma, the IL‐18 expression was not different in the lamina propria compared with controls but was decreased in the epithelium. In contrast, the IL‐18BP was decreased in the lamina propria in asthma and was absent in the bronchial epithelium. IL‐18 was released in sputum with IL‐18BP elevated in patients with asthma. The IL‐18Rα expression was not different between health and disease. In vitro, IL‐18‐stimulated bronchial epithelial cells increased intracellular calcium, wound repair, metabolic activity, morphological changes and epithelial cellular differentiation. CONCLUSION: In asthma, the dynamic interaction between IL‐18, its cognate receptor and natural inhibitor is complex, with differences between airway compartments. Upregulation of IL‐18 can promote epithelial activation and cellular differentiation.