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

作者：Murai Hiroki^*; Qi Huibin; Choudhury Barun; Wild Jim; Dharajiya Nilesh; Vaidya Swapnil; Kalita Anjana; Bacsi Attila; Corry David; Kurosky Alexander; Brasier Allan; Boldogh Istvan; Sur Sanjiv

来源：PLos One, 2012, 7(2): e30280.

DOI：10.1371/journal.pone.0030280

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. %26lt;br%26gt;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 naive 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 naive CD4 cells with rmIL-18 induced Th2 differentiation in the absence of IL-4 and STAT6, and this effect was abrogated by disrupting NF-kappa B p50 or with a NEMO binding peptide inhibitor. %26lt;br%26gt;Conclusion/Significance: Rapid and specific release of IL-18 from Alternaria-exposed damaged airway epithelial cells can directly initiate Th2 differentiation of naive CD4(+) T-cells via a unique NF-kappa B dependent pathway.

• 出版日期2012-2-7