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Abrogation of Anti-Inflammatory Transcription Factor LKLF in Neutrophil-Dominated Airways

¹ Division of Pulmonary Sciences and Critical Care Medicine, and ⁴ Division of Infectious Diseases, University of Colorado School of Medicine, Denver, Colorado; ³ Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado; ² Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Correspondence and requests for reprints should be addressed to Milene T. Saavedra, M.D., University of Colorado Health Sciences Center, 4200 E. Ninth Avenue, Box C272, Denver, CO 80262. E-mail: milene.saavedra{at}uchsc.edu

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 airway diseases, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease. LKLF from primary airway epithelial cells inhibits NF-B–driven transcription induced by Pseudomonas aeruginosa 7-fold, but is down-regulated in the presence of 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.

Key Words: Lung Kruppel-like Factor • cystic fibrosis • bronchial epithelium • human neutrophils • airway inflammation

CLINICAL RELEVANCE This is the first report describing the absence of anti-inflammatory transcription factor Lung Kruppel-like Factor from the lungs of patients suffering from cystic fibrosis (CF), contributing new data supporting the pathophysiology of constitutive inflammation in CF lung disease.