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American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 561-567, 2002
© 2002 American Thoracic Society
DOI: 10.1165/rcmb.2002-0019OC

Bacterial Stimulation of Epithelial G-CSF and GM-CSF Expression Promotes PMN Survival in CF Airways

Shahryar Saba, Grace Soong, Steven Greenberg and Alice Prince

College of Physicians and Surgeons, Columbia University, New York, New York

Address correspondence to: Alice Prince, Black Building 416, 650 West 168th Street, New York, NY 10032. E-mail: asp7{at}columbia.edu

Airway epithelial cells provide an immediate response to bacterial pathogens by producing chemokines and cytokines that recruit polymorphonuclear leukocytes (PMNs) to the site of infection. This response is excessive in patients with cystic fibrosis (CF) who have bacterial contamination of their airways. We postulated that CF airway pathogens, in activating nuclear factor-{kappa}B–dependent gene transcription in epithelial cells, would promote expression of cytokines that inhibit constitutive apoptosis of recruited PMNs. Epithelial cell culture supernatants from CF (IB-3) and corrected (C-38) epithelial cells stimulated by Staphylococcus aureus or Pseudomonas aeruginosa, increased survival of PMNs by 2- to 5-fold. Enhanced PMN survival was attributed to effects of epithelial granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor expression, which inhibit PMN apoptosis, and was negated by neutralizing antibody to either cytokine. Both CF and normal cells responded to bacteria with increased cytokine production. Granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor expression were activated by ligation of asialoGM1, a receptor for P. aeruginosa and S. aureus, and by S. aureus lipoteichoic acid. Lipopolysaccharide was not a potent stimulus of cytokine expression, and P. aeruginosa algC (lipopolysaccharide) and lasR (quorum sensing) mutants were fully capable of activating epithelial cells. Induced expression of cytokines by airway cells repeatedly exposed to bacteria, as occurs in CF, serves not only to recruit and activate PMNs, but also to enhance their survival.

Abbreviations: cystic fibrosis, CF • transmembrane conductance regulator, CFTR • conditioned media, CM • extracellular signal-related kinase, ERK • fetal calf serum, FCS • granulocyte colony-stimulating factor, G-CSF • granulocyte–macrophage colony-stimulating factor, GM-CSF • mitogen activated protein kinase, MAPK • nuclear factor-kB, NF-kB • polymorphonuclear leukocytes, PMNs • reverse transcriptase-polymerase chain reaction, RT-PCR • tumor necrosis factor-{alpha}, TNF-{alpha}




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