Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFκB

Abstract

The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) is important for the initiation of allergic airway inflammation through a dendritic cell-mediated T helper 2 response. To identify the factors that control TSLP expression, we examined the ability of inflammatory mediators to regulate TSLP production in human airway epithelial cells. We found that both IL-1β and TNF-α were capable of inducing rapid TSLP production in primary human bronchial airway epithelial cells. We further characterized the human TSLP gene promoter, using two human epithelial cell lines, 16HBEo−and A549, and showed that IL-1β- and TNF-α-mediated human TSLP promoter activation in these cells was mediated by an upstream NFκB site. Mutation of this NFκB site abolished activation, as did overexpression of a dominant-negative version of IκB kinase (IKK)β (a kinase acting on IκB, the inhibitor of NFκB). Interestingly, human TSLP mRNA levels were also increased after exposure to Toll-like receptor (TLR) 2, TLR8, and TLR9 ligands, further supporting an important role for NFκB in TSLP gene regulation. Similarly, analysis of the mouse TSLP gene promoter revealed the presence of a similarly situated NFκB site that was also critical for IL-1β-inducible expression of mouse TSLP. Taken together, these results demonstrate that the inflammatory mediators IL-1β and TNF-α regulate human TSLP gene expression in an NFκB-dependent manner.