title: Alternaria-induced release of IL-18 from damaged airway epithelial cells: an NF-κB dependent mechanism of Th2 differentiation?
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Murai
authors.forename: Huibin
authors.initials: H
authors.lastname: Qi
authors.forename: Barun
authors.initials: B
authors.lastname: Choudhury
authors.forename: Jim
authors.initials: J
authors.lastname: Wild
authors.forename: Nilesh
authors.initials: N
authors.lastname: Dharajiya
authors.forename: Swapnil
authors.initials: S
authors.lastname: Vaidya
authors.forename: Anjana
authors.initials: A
authors.lastname: Kalita
authors.forename: Attila
authors.initials: A
authors.lastname: Bacsi
authors.forename: David
authors.initials: D
authors.lastname: Corry
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurosky
authors.forename: Allan
authors.initials: A
authors.lastname: Brasier
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Sur
mesh_terms: D000528:Alternaria / Q000276:immunology*; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis; D004847:Epithelial Cells / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000276:immunology*; D009336:Necrosis; D012137:Respiratory System / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology*
chemical_list: D016207:Cytokines; D020382:Interleukin-18; D016328:NF-kappa B