Abstract: This is the first report to describe a role for Lung Kruppel-like Factor (LKLF or KLF2) in inflammatory airways diseases. In the present study, we identify that LKLF is constitutively expressed in the small airways of normal lungs; however, its expression disappears in severe airways diseases, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). LKLF from primary airway epithelial cells inhibits NF-B-driven transcription induced by Pseudomonas aeruginosa seven-fold but is downregulated in the presence of tumor necrosis factor-alpha (TNF) and activated human neutrophils. As a constitutively expressed protein, LKLF inhibits release of a key pro-inflammatory chemokine, IL-8, from airway epithelia. Its expression by lung epithelial cells is enhanced in the presence of TNF blockade. Thus, cytokine mediated inhibition of LKLF by neutrophils may contribute to ongoing recruitment by promoting IL-8 release from airway epithelia. We conclude that, in neutrophil dominated airway environments, such as that seen in CF, reduced LKLF activity releases a brake on pro-inflammatory cytokine production and thereby may contribute to the persistent inflammatory responses seen in CF airway disease.