Abrogation of anti-inflammatory transcription factor LKLF in neutrophil-dominated airways.
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-kappaB-driven transcription induced by Pseudomonas aeruginosa 7-fold, but is down-regulated in the presence of TNF-alpha 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.
Saavedra
Milene T
MT
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado, USA. milene.saavedra@uchsc.edu
Patterson
Abby D
AD
West
James
J
Randell
Scott H
SH
Riches
David W
DW
Malcolm
Ken C
KC
Cool
Carlyne D
CD
Nick
Jerry A
JA
Dinarello
Charles A
CA
D000328:Adult; D002460:Cell Line; D002648:Child; D003550:Cystic Fibrosis / Q000276:immunology; D004789:Enzyme Activation; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020545:Respiratory Mucosa / Q000166:cytology* / Q000276:immunology / Q000473:pathology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D016209:Interleukin-8; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II