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

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-1 beta and TNF-alpha 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-1 beta- and TNIF-alpha-mediated human TSLP promoter activation in these cells was mediated by an upstream NF kappa B site. Mutation of this NF kappa B site abolished activation, as did overexpression of a dominant-negative version of 116 kinase (IKK)beta (a kinase acting on I kappa B, the inhibitor of NF kappa B). 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 NF kappa B in TSLP gene regulation. Similarly, analysis of the mouse TSLP gene promoter revealed the presence of a similarly situated NF kappa B site that was also critical for IL-1 beta-inducible expression of mouse TSLP. Taken together, these results demonstrate that the inflammatory mediators IL-1 beta and TNF-alpha regulate human TSLP gene expression in an NF kappa B-dependent manner.