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Background  A series of epidemiologic studies have identified the fungus  Alternaria  as a major risk factor for asthma. The airway epithelium plays a critical role in the pathogenesis of allergic asthma. These reports suggest that activated airway epithelial cells can produce cytokines such as IL-25, TSLP and IL-33 that induce Th2 phenotype. However the epithelium-derived products that mediate the pro-asthma effects of  Alternaria  are not well characterized. We hypothesized that exposure of the airway epithelium to  Alternaria  releasing cytokines that can induce Th2 differentiation.    Methodology/Principal Finding  We used ELISA to measure human and mouse cytokines.  Alternaria  extract (ALT-E) induced rapid release of IL-18, but not IL-4, IL-9, IL-13, IL-25, IL-33, or TSLP from cultured normal human bronchial epithelial cells; and in the BAL fluids of naïve mice after challenge with ALT-E. Both microscopic and FACS indicated that this release was associated with necrosis of epithelial cells. ALT-E induced much greater IL-18 release compared to 19 major outdoor allergens. Culture of naïve CD4 cells with rmIL-18 induced Th2 differentiation in the absence of IL-4 and STAT6, and this effect was abrogated by disrupting NF- κB p50 or with a NEMO binding peptide inhibitor.    Conclusion/Significance  Rapid and specific release of IL-18 from Alternaria-exposed damaged airway epithelial cells can directly initiate Th2 differentiation of naïve CD4 +  T-cells via a unique NF-κB dependent pathway.

Alternaria-Induced Release of IL-18 from Damaged Airway Epithelial Cells: An NF-κB Dependent Mechanism of Th2 Differentiation?