House Dust Mite Allergens and the Induction of Monocyte Interleukin 1β Production That Triggers an IκBζ-Dependent Granulocyte Macrophage Colony-Stimulating Factor Release from Human Lung Epithelial Cells

摘要

Asthma is a chronic lung disease characterized by inflammation centered upon bronchial epithelium. House dust mite is one of the most common respiratory allergens that trigger exacerbations of asthma. IκBζ (gene NFKBIZ) is a recently recognized member of the NF-κB family that can be induced in mononuclear phagocytes and lung epithelial cells and has been shown to play a prominent role in epithelial cell function. We therefore analyzed the role of IκBζ in regulating lung epithelial cell cytokine responses to house dust mite mix (HDM). We found that human bronchial epithelial cells express IκBζ and release IL-6 and granulocyte macrophage colony-stimulating factor (GMCSF) when cocultured with human monocytes and HDM. This response is blocked in the presence of IL-1 receptor antagonist (IL-1Ra), indicating that it is IL-1 mediated. Neither HDM-stimulated macrophages nor dendritic cells release IL-1β and subsequently induce cytokine release from the bronchial epithelial cells. Rhodobacter sphaeroides LPS (RS-LPS), a TLR4 antagonist, blocks the ability of HDM to induce IκBζ and release GMCSF from epithelial cells cocultured with monocytes. Additionally, human bronchial epithelial cells show no induction of IκBζ or cytokine responses to direct HDM stimulation. Finally, NFKBIZ small interfering RNA–mediated knockdown in the bronchial epithelial cells suppresses the release of IL-1–induced IL-6 and GMCSF. Our findings indicate a possible role for monocyte recruitment and lung epithelial cell IκBζ in mediating asthma associated inflammation. Thus, IκBζ, IL-1Ra, and RS-LPS deserve future study as potential modulators of house dust mite–induced asthma.